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Xu X, Li X, Zhai C, Yao Y, Li X, Ming C, Sun J, Wang H, Mao Y, Zhang L. Intravenous injection of PCSK9 gain-of-function mutation in C57BL/6J background mice on Angiotensin II-induced AAA. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167657. [PMID: 39765329 DOI: 10.1016/j.bbadis.2025.167657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/16/2024] [Accepted: 01/02/2025] [Indexed: 02/20/2025]
Abstract
OBJECTIVE This study was performed to compare the incidence of Angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) between intravenous and intraperitoneal injection of AAV8.mPCSK9D377Y in wild-type (WT) mice with C57BL/6J background and the pathological differences of above model in WT and ApoE-/- mice. DESIGN Male WT mice were injected intraperitoneally or intravenously with either a AAV8.null or AAV8.mPCSK9D377Y. Two weeks after injection, all WT mice were infused with Ang II, and simultaneously age-matched male ApoE-/- mice were infused with saline or Ang II for 4 weeks. RESULTS Compared with intraperitoneal injection of AAV8.mPCSK9D377Y for AAA model in WT mice, a higher incidence of Ang II-induced AAA, increased blood pressure (BP) and lipid concentration, lower collagen deposition and up-regulated inflammation response were shown by intravenous injection, which was similar to ApoE-/- mice infused with Ang II. CONCLUSION AAV8.mPCSK9D377Y infected male WT mice intravenously facilitate a high incident and comparable severity of Ang II-induced AAA which could be greatly expedites AAA studies on a gene of interest.
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Affiliation(s)
- Xingli Xu
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaohui Li
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Chungang Zhai
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yuxin Yao
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiang Li
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Chunjie Ming
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Juanjuan Sun
- Hepatology Department II, Qingdao Sixth People's Hospital, No. 9 Fushun Road, Qingdao, Shandong 266033, China
| | - Hao Wang
- Department of Critical Care Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong 250012, China.
| | - Yang Mao
- Department of Critical Care Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, Shandong 250012, China.
| | - Lei Zhang
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
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Hong L, Yue H, Cai D, DeHart A, Toloza-Alvarez G, Du L, Zhou X, Fan X, Huang H, Chen S, Rahaman SO, Zhuang J, Li W. Thymidine Phosphorylase Promotes Abdominal Aortic Aneurysm via VSMC Modulation and Matrix Remodeling in Mice and Humans. Cardiovasc Ther 2024; 2024:1129181. [PMID: 39742002 PMCID: PMC11669429 DOI: 10.1155/cdr/1129181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/25/2024] [Indexed: 01/03/2025] Open
Abstract
Background: Thymidine phosphorylase (TYMP) promotes platelet activation and thrombosis while suppressing vascular smooth muscle cell (VSMC) proliferation. Both processes are central to the development and progression of abdominal aortic aneurysms (AAAs). We hypothesize that TYMP plays a role in AAA development. Methods: Male wild-type (WT) C57BL/6J and Tymp-/- mice, fed a Western diet (WD) (TD.88137), were subjected to the 4-week Ang II infusion-induced AAA model. AAA progression was monitored by echography and confirmed through necropsy. Whole-body inflammation was assessed using a plasma cytokine array. Mechanistic studies were conducted using TYMP-overexpressing rat VSMC cell lines and primary VSMCs cultured from WT and Tymp-/- mouse thoracic aortas. Histological studies were performed on human AAA and normal aorta samples. Results: Elevated TYMP levels were observed in human AAA vessel walls. While WT mice exhibited a 28.6% prevalence of Ang II infusion-induced AAA formation, Tymp-/- mice were protected. TYMP enhanced MMP2 expression, secretion, and activation in VSMCs, which was inhibited by tipiracil, a selective TYMP inhibitor. Systemically, TYMP promoted proinflammatory cytokine expression, and its absence attenuated TNF-α-induced MMP2 and AKT activation. WT VSMCs treated with platelets lacking TYMP showed a higher proliferation rate than cells treated with WT platelets. Additionally, TYMP increased activated TGFβ1 expression in cultured VSMCs and human AAA vessel walls. In WT VSMCs, TYMP augmented thrombospondin-1 type 1 repeat domain (TSR)-stimulated TGFβ1 signaling, increasing connective tissue growth factor and MMP2 production. TSR also enhanced AKT activation in WT VSMCs but had the opposite effect in Tymp-/- cells. TSR-enhanced MMP2 activation in WT VSMCs was attenuated by LY294002 (a PI3K inhibitor) but not by SB431542 (a TGFβ1 inhibitor); both inhibitors had indiscernible effects on Tymp-/- VSMC. Conclusion: TYMP emerges as a novel regulatory force in vascular biology, influencing VSMC function and inflammatory responses to promote AAA development.
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MESH Headings
- Aortic Aneurysm, Abdominal/enzymology
- Aortic Aneurysm, Abdominal/pathology
- Aortic Aneurysm, Abdominal/chemically induced
- Aortic Aneurysm, Abdominal/genetics
- Aortic Aneurysm, Abdominal/metabolism
- Animals
- Mice, Inbred C57BL
- Male
- Humans
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Mice, Knockout
- Disease Models, Animal
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/drug effects
- Vascular Remodeling
- Aorta, Abdominal/pathology
- Aorta, Abdominal/enzymology
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/drug effects
- Thymidine Phosphorylase/genetics
- Thymidine Phosphorylase/metabolism
- Signal Transduction
- Matrix Metalloproteinase 2/metabolism
- Matrix Metalloproteinase 2/genetics
- Angiotensin II
- Cells, Cultured
- Inflammation Mediators/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Transforming Growth Factor beta1/metabolism
- Transforming Growth Factor beta1/genetics
- Rats
- Extracellular Matrix/metabolism
- Extracellular Matrix/enzymology
- Extracellular Matrix/pathology
- Cell Line
- Disease Progression
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Affiliation(s)
- Liang Hong
- Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
| | - Hong Yue
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
| | - Dunpeng Cai
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Autumn DeHart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
| | - Gretel Toloza-Alvarez
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
| | - Lili Du
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
| | - Xianwu Zhou
- Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoping Fan
- Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Huanlei Huang
- Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Shiyou Chen
- Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA
- The Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, USA
| | - Shaik O. Rahaman
- Department of Nutrition and Food Science, University of Maryland, College Park, Maryland, USA
| | - Jian Zhuang
- Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA
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Wu H, Li Z, Yang L, He L, Liu H, Yang S, Xu Q, Li Y, Li W, Li Y, Gong Z, Shen Y, Yang X, Huang J, Yu F, Li L, Zhu J, Sun L, Fu Y, Kong W. ANK Deficiency-Mediated Cytosolic Citrate Accumulation Promotes Aortic Aneurysm. Circ Res 2024; 135:1175-1192. [PMID: 39513269 DOI: 10.1161/circresaha.124.325152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND Disturbed metabolism and transport of citrate play significant roles in various pathologies. However, vascular citrate regulation and its potential role in aortic aneurysm (AA) development remain poorly understood. METHODS Untargeted metabolomics by mass spectrometry was applied to identify upregulated metabolites of the tricarboxylic acid cycle in AA tissues of mice. To investigate the role of citrate and its transporter ANK (progressive ankylosis protein) in AA development, vascular smooth muscle cell (VSMC)-specific Ank-knockout mice were used in both Ang II (angiotensin II)- and CaPO4-induced AA models. RESULTS Citrate was abnormally increased in both human and murine aneurysmal tissues, which was associated with downregulation of ANK, a citrate membrane transporter, in VSMCs. The knockout of Ank in VSMCs promoted AA formation in both Ang II- and CaPO4-induced AA models, while its overexpression inhibited the development of aneurysms. Mechanistically, ANK deficiency in VSMCs caused abnormal cytosolic accumulation of citrate, which was cleaved into acetyl coenzyme A and thus intensified histone acetylation at H3K23, H3K27, and H4K5. Cleavage under target and tagmentation analysis further identified that ANK deficiency-induced histone acetylation activated the transcription of inflammatory genes in VSMCs and thus promoted a citrate-related proinflammatory VSMC phenotype during aneurysm diseases. Accordingly, suppressing citrate cleavage to acetyl coenzyme A downregulated inflammatory gene expression in VSMCs and restricted ANK deficiency-aggravated AA formation. CONCLUSIONS Our studies define the pathogenic role of ANK deficiency-induced cytosolic citrate accumulation in AA pathogenesis and an undescribed citrate-related proinflammatory VSMC phenotype. Targeting ANK-mediated citrate transport may emerge as a novel diagnostic and therapeutic strategy in AA.
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MESH Headings
- Animals
- Mice
- Citric Acid/metabolism
- Humans
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Mice, Knockout
- Aortic Aneurysm/metabolism
- Aortic Aneurysm/genetics
- Aortic Aneurysm/pathology
- Aortic Aneurysm/etiology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Mice, Inbred C57BL
- Cytosol/metabolism
- Male
- Cells, Cultured
- Acetylation
- Acetyl Coenzyme A/metabolism
- Disease Models, Animal
- Histones/metabolism
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Affiliation(s)
- Hao Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Zhiqing Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Liu Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China (L.Y.)
| | - Lin He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Hao Liu
- Department of Cardiovascular Surgery, Beijing Aortic Disease Center, Beijing Anzhen Hospital, Capital Medical University, China (H.L., Q.X., J.Z.)
| | - Shiyu Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Qinfeng Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yanjie Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Wenqiang Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yiran Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Ze Gong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
- Hwamei College of Life and Health Sciences, Zhejiang Wanli University, Ningbo, China (Z.G.)
| | - Yicong Shen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xueyuan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jiaqi Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Fang Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Li Li
- Department of Pathology, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (L.L.)
| | - Junming Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Luyang Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling (H.W., Z.L., L.Y., S.Y., Yanjie Li, W.L., Yiran Li, Z.G., Y.S., X.Y., J.H., F.Y., Y.F., W.K.), School of Basic Medical Sciences, Peking University, Beijing, China
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Sharma N, Khalyfa A, Cai D, Morales-Quinones M, Soares RN, Higashi Y, Chen S, Gozal D, Padilla J, Manrique-Acevedo C, Chandrasekar B, Martinez-Lemus LA. Chronic intermittent hypoxia facilitates the development of angiotensin II-induced abdominal aortic aneurysm in male mice. J Appl Physiol (1985) 2024; 137:527-539. [PMID: 38867666 PMCID: PMC11424178 DOI: 10.1152/japplphysiol.00842.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 04/11/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024] Open
Abstract
Obstructive sleep apnea (OSA), characterized by episodes of intermittent hypoxia (IH), is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, whether IH serves as an independent risk factor for AAA development remains to be investigated. Here, we determined the effects of chronic (6 mo) IH on angiotensin (Ang II)-induced AAA development in C57BL/6J male mice and investigated the underlying mechanisms of IH in cultured vascular smooth muscle cells (SMCs). IH increased the susceptibility of mice to develop AAA in response to Ang II infusion by facilitating the augmentation of the abdominal aorta's diameter as assessed by transabdominal ultrasound imaging. Importantly, IH with Ang II augmented aortic elastin degradation and the expression of matrix metalloproteinases (MMPs), mainly MMP8, MMP12, and a disintegrin and metalloproteinase-17 (ADAM17) as measured by histology and immunohistochemistry. Mechanistically, IH increased the activities of MMP2, MMP8, MMP9, MMP12, and ADAM17, while reducing the expression of the MMP regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in cultured SMCs. Aortic samples from human AAA were associated with decreased RECK and increased expression of ADAM17 and MMPs. These data suggest that IH facilitates AAA development when additional stressors are superimposed and that this occurs in association with an increased presence of aortic MMPs and ADAM17, potentially due to IH-induced modulation of RECK expression. These findings support a plausible synergistic link between OSA and AAA and provide a better understanding of the molecular mechanisms underlying the pathogenesis of AAA.NEW & NOTEWORTHY IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs.
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MESH Headings
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/chemically induced
- Aortic Aneurysm, Abdominal/pathology
- Animals
- Male
- Angiotensin II
- Mice, Inbred C57BL
- Hypoxia/metabolism
- Hypoxia/complications
- Mice
- ADAM17 Protein/metabolism
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/pathology
- Myocytes, Smooth Muscle/metabolism
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Humans
- Matrix Metalloproteinases/metabolism
- Matrix Metalloproteinase 12/metabolism
- Sleep Apnea, Obstructive/metabolism
- Sleep Apnea, Obstructive/physiopathology
- Sleep Apnea, Obstructive/complications
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Affiliation(s)
- Neekun Sharma
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
- Department of Medicine, Center for Precision Medicine, University of Missouri, Columbia, Missouri, United States
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri, United States
| | - Abdelnaby Khalyfa
- Department of Child Health and the Child Health Research Institute, School of Medicine, University of Missouri, Columbia, Missouri, United States
| | - Dunpeng Cai
- Department of Surgery, University of Missouri, Columbia, Missouri, United States
| | | | - Rogerio N Soares
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
| | - Yusuke Higashi
- John W. Deming Department of Medicine, Tulane University, New Orleans, Louisiana, United States
| | - Shiyou Chen
- Department of Surgery, University of Missouri, Columbia, Missouri, United States
- Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States
| | - David Gozal
- Department of Child Health and the Child Health Research Institute, School of Medicine, University of Missouri, Columbia, Missouri, United States
| | - Jaume Padilla
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
- Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
| | - Camila Manrique-Acevedo
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri, United States
- Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States
| | - Bysani Chandrasekar
- Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, United States
- Division of Cadiovascular Medicine, Department of Medicine, University of Missouri, Columbia, Missouri, United States
| | - Luis A Martinez-Lemus
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
- Department of Medicine, Center for Precision Medicine, University of Missouri, Columbia, Missouri, United States
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States
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5
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Barkhordarian M, Tran HHV, Menon A, Pulipaka SP, Aguilar IK, Fuertes A, Dey S, Chacko AA, Sethi T, Bangolo A, Weissman S. Innovation in pathogenesis and management of aortic aneurysm. World J Exp Med 2024; 14:91408. [PMID: 38948412 PMCID: PMC11212750 DOI: 10.5493/wjem.v14.i2.91408] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/04/2024] [Accepted: 03/18/2024] [Indexed: 06/19/2024] Open
Abstract
Aortic aneurysm (AA) refers to the persistent dilatation of the aorta, exceeding three centimeters. Investigating the pathophysiology of this condition is important for its prevention and management, given its responsibility for more than 25000 deaths in the United States. AAs are classified based on their location or morphology. various pathophysiologic pathways including inflammation, the immune system and atherosclerosis have been implicated in its development. Inflammatory markers such as transforming growth factor β, interleukin-1β, tumor necrosis factor-α, matrix metalloproteinase-2 and many more may contribute to this phenomenon. Several genetic disorders such as Marfan syndrome, Ehler-Danlos syndrome and Loeys-Dietz syndrome have also been associated with this disease. Recent years has seen the investigation of novel management of AA, exploring the implication of different immune suppressors, the role of radiation in shrinkage and prevention, as well as minimally invasive and newly hypothesized surgical methods. In this narrative review, we aim to present the new contributing factors involved in pathophysiology of AA. We also highlighted the novel management methods that have demonstrated promising benefits in clinical outcomes of the AA.
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Affiliation(s)
- Maryam Barkhordarian
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Hadrian Hoang-Vu Tran
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Aiswarya Menon
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Sai Priyanka Pulipaka
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Izage Kianifar Aguilar
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Axel Fuertes
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shraboni Dey
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Angel Ann Chacko
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Tanni Sethi
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Ayrton Bangolo
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Simcha Weissman
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
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Di Gregoli K, Atkinson G, Williams H, George SJ, Johnson JL. Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice. Int J Mol Sci 2024; 25:5809. [PMID: 38891996 PMCID: PMC11172660 DOI: 10.3390/ijms25115809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/21/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
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Affiliation(s)
| | | | | | | | - Jason L. Johnson
- Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK; (K.D.G.); (G.A.); (H.W.); (S.J.G.)
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7
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Hong L, Yue H, Cai D, DeHart A, Toloza-Alvarez G, Du L, Zhou X, Fan X, Huang H, Chen S, Rahaman SO, Zhuang J, Li W. Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.27.582208. [PMID: 38464026 PMCID: PMC10925194 DOI: 10.1101/2024.02.27.582208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Aims The precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development. Methods and Results We conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) and Tymp-/- mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found that Tymp-/- mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT and Tymp-/- mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production. Conclusion Our findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.
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Affiliation(s)
- Liang Hong
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV
| | - Hong Yue
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV
| | - Dunpeng Cai
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO
| | - Autumn DeHart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV
| | - Gretel Toloza-Alvarez
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV
| | - Lili Du
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV
| | - Xianwu Zhou
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoping Fan
- Department of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Huanlei Huang
- Department of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Shiyou Chen
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO
- The Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO
| | - Shaik O. Rahaman
- University of Maryland, Department of Nutrition and Food Science, College Park, MD
| | - Jian Zhuang
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV
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8
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Vanmaele A, Bouwens E, Hoeks SE, Kindt A, Lamont L, Fioole B, Moelker A, Ten Raa S, Hussain B, Oliveira-Pinto J, Ijpma AS, van Lier F, Akkerhuis KM, Majoor-Krakauer DF, Hankemeier T, de Rijke Y, Verhagen HJ, Boersma E, Kardys I. Targeted proteomics and metabolomics for biomarker discovery in abdominal aortic aneurysm and post-EVAR sac volume. Clin Chim Acta 2024; 554:117786. [PMID: 38246209 DOI: 10.1016/j.cca.2024.117786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 12/27/2023] [Accepted: 01/14/2024] [Indexed: 01/23/2024]
Abstract
BACKGROUND AND AIMS Abdominal aortic aneurysm (AAA) patients undergo uniform surveillance programs both leading up to, and following surgery. Circulating biomarkers could play a pivotal role in individualizing surveillance. We applied a multi-omics approach to identify relevant biomarkers and gain pathophysiological insights. MATERIALS AND METHODS In this cross-sectional study, 108 AAA patients and 200 post-endovascular aneurysm repair (post-EVAR) patients were separately investigated. We performed partial least squares regression and ingenuity pathway analysis on circulating concentrations of 96 proteins (92 Olink Cardiovascular-III panel, 4 ELISA-assays) and 199 metabolites (measured by LC-TQMS), and their associations with CT-based AAA/sac volume. RESULTS The median (25th-75th percentile) maximal diameter was 50.0 mm (46.0, 53.0) in the AAA group, and 55.4 mm (45.0, 64.2) in the post-EVAR group. Correcting for clinical characteristics in AAA patients, the aneurysm volume Z-score differed 0.068 (95 %CI: (0.042, 0.093)), 0.066 (0.047, 0.085) and -0.051 (-0.064, -0.038) per Z-score valine, leucine and uPA, respectively. After correcting for clinical characteristics and orthogonalization in the post-EVAR group, the sac volume Z-score differed 0.049 (0.034, 0.063) per Z-score TIMP-4, -0.050 (-0.064, -0.037) per Z-score LDL-receptor, -0.051 (-0.062, -0.040) per Z-score 1-OG/2-OG and -0.056 (-0.066, -0.045) per Z-score 1-LG/2-LG. CONCLUSIONS The branched-chain amino acids and uPA were related to AAA volume. For post-EVAR patients, LDL-receptor, monoacylglycerols and TIMP-4 are potential biomarkers for sac volume. Additionally, distinct markers for sac change were identified.
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Affiliation(s)
- Alexander Vanmaele
- Department of Cardiology, Thorax Centre, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, the Netherlands
| | - Elke Bouwens
- Department of Cardiology, Thorax Centre, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, the Netherlands; Department of Anesthesiology, Erasmus MC, Rotterdam, the Netherlands
| | - Sanne E Hoeks
- Department of Anesthesiology, Erasmus MC, Rotterdam, the Netherlands
| | - Alida Kindt
- Metabolomics and Analytics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - Lieke Lamont
- Metabolomics and Analytics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - Bram Fioole
- Department of Vascular Surgery, Maasstad Hospital, Rotterdam, the Netherlands
| | - Adriaan Moelker
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Sander Ten Raa
- Department of Vascular Surgery, Erasmus MC, Rotterdam, the Netherlands
| | - Burhan Hussain
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Radiology, Beatrix hospital, Gorinchem, the Netherlands
| | - José Oliveira-Pinto
- Department of Vascular Surgery, Erasmus MC, Rotterdam, the Netherlands; Department of Angiology and Vascular Surgery, Centro Hospitalar São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine of Oporto, Porto, Portugal
| | - Arne S Ijpma
- Department of Pathology, Erasmus MC, Rotterdam, the Netherlands
| | - Felix van Lier
- Department of Anesthesiology, Erasmus MC, Rotterdam, the Netherlands
| | - K Martijn Akkerhuis
- Department of Cardiology, Thorax Centre, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands
| | | | - Thomas Hankemeier
- Metabolomics and Analytics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - Yolanda de Rijke
- Department of Clinical Chemistry, Erasmus MC, Rotterdam, the Netherlands
| | - Hence Jm Verhagen
- Department of Vascular Surgery, Erasmus MC, Rotterdam, the Netherlands
| | - Eric Boersma
- Department of Cardiology, Thorax Centre, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands
| | - Isabella Kardys
- Department of Cardiology, Thorax Centre, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands.
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9
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Puertas-Umbert L, Almendra-Pegueros R, Jiménez-Altayó F, Sirvent M, Galán M, Martínez-González J, Rodríguez C. Novel pharmacological approaches in abdominal aortic aneurysm. Clin Sci (Lond) 2023; 137:1167-1194. [PMID: 37559446 PMCID: PMC10415166 DOI: 10.1042/cs20220795] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/05/2023] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.
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Affiliation(s)
- Lídia Puertas-Umbert
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
| | | | - Francesc Jiménez-Altayó
- Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marc Sirvent
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Departamento de Angiología y Cirugía Vascular del Hospital Universitari General de Granollers, Granollers, Barcelona, Spain
| | - María Galán
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain
| | - José Martínez-González
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
- Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Barcelona, Spain
| | - Cristina Rodríguez
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
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10
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Qiu C, Li Y, Xiao L, Zhang J, Guo S, Zhang P, Li R, Gong K. A novel rabbit model of abdominal aortic aneurysm: Construction and evaluation. Heliyon 2023; 9:e17279. [PMID: 37389075 PMCID: PMC10300360 DOI: 10.1016/j.heliyon.2023.e17279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
Prior research has indicated that animal models of abdominal aortic aneurysm (AAA) utilizing porcine pancreatic elastase (PPE) exhibit a perfusion duration of 30 min, and extended perfusion durations are associated with elevated mortality rates. Similarly, the AAA model, which relies solely on balloon dilation (BD), is limited by the occurrence of self-healing aneurysms. Consequently, we constructed a novel AAA model by PPE combined with balloon expansion to shorten the modeling time and improve the modeling success rate. The findings indicated that 5 min was the optimal BD time for rabbits, 3 min BD was ineffective for aneurysm formation, and 10 min BD had a high mortality rate. The model, constructed in combination with PPE and 5 min BD, exhibited a 100% model formation rate and a 244.7% ± 9.83% dilation rate. HE staining exhibited that severe disruption of the inner, middle, and outer membranes of the abdominal aorta, with a marked decrease in smooth muscle cells and elastase, and a marked increase in fibroblasts of the middle membrane, and many infiltrating inflammatory cells were seen in all three layers, especially in the middle membrane. EVG staining displayed that the elastic fibers of the abdominal aortic wall were fractured and degraded, and lost their normal wavy appearance. The protein expression of inflammatory factor (IL-1β, IL-6 and TNF-α) as well as extracellular matrix components (MMP-2 and MMP-9) were significantly increased compared to PPE and 5 min BD alone. In conclusion, PPE combined with BD allows the establishment of a novel AAA model that closely mimics human AAA in terms of histomorphology, inflammatory cell infiltration, and vascular stromal destruction. This model provides an ideal animal model for understanding the pathogenesis of AAA.
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Affiliation(s)
- Changtao Qiu
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Yuejin Li
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Le Xiao
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Jian Zhang
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Shikui Guo
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Peng Zhang
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Ruoxi Li
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
| | - Kunmei Gong
- Department of General Surgery, The First People’s Hospital of Yunnan Province Kunming, Kunming, 650032, Yunnan, China
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11
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Ashida S, Yamawaki-Ogata A, Tokoro M, Mutsuga M, Usui A, Narita Y. Administration of anti-inflammatory M2 macrophages suppresses progression of angiotensin II-induced aortic aneurysm in mice. Sci Rep 2023; 13:1380. [PMID: 36697439 PMCID: PMC9877022 DOI: 10.1038/s41598-023-27412-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/02/2023] [Indexed: 01/27/2023] Open
Abstract
Aortic aneurysm (AA) is a vascular disorder characterized pathologically by inflammatory cell invasion and extracellular matrix (ECM) degradation. It is known that regulation of the balance between pro-inflammatory M1 macrophages (M1Ms) and anti-inflammatory M2 macrophages (M2Ms) plays a pivotal role in AA stabilization. We investigated the effects of M2M administration in an apolipoprotein E-deficient (apoE-/-) mouse model in which AA was induced by angiotensin II (ATII) infusion. Mice received intraperitoneal administration of 1 million M2Ms 4 weeks after ATII infusion. Compared with a control group that was administered saline, the M2M group exhibited reduced AA expansion; decreased expression levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1); and a lower M1M/M2M ratio. Moreover, the M2M group exhibited upregulation of anti-inflammatory factors, including IL-4 and IL-10. PKH26-labeled M2Ms accounted for 6.5% of cells in the aneurysmal site and co-expressed CD206. Taken together, intraperitoneal administration of M2Ms inhibited AA expansion by reducing the inflammatory reaction via regulating the M1M/M2M ratio. This study shows that M2M administration might be useful for the treatment of AA.
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Affiliation(s)
- Shinichi Ashida
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Aika Yamawaki-Ogata
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Masayoshi Tokoro
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Masato Mutsuga
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Akihiko Usui
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Yuji Narita
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
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12
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Boxhammer E, Hecht S, Kaufmann R, Kammler J, Kellermair J, Reiter C, Akbari K, Blessberger H, Steinwender C, Lichtenauer M, Hoppe UC, Hergan K, Scharinger B. The Presence of Ascending Aortic Dilatation in Patients Undergoing Transcatheter Aortic Valve Replacement Is Negatively Correlated with the Presence of Diabetes Mellitus and Does Not Impair Post-Procedural Outcomes. Diagnostics (Basel) 2023; 13:diagnostics13030358. [PMID: 36766463 PMCID: PMC9914357 DOI: 10.3390/diagnostics13030358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
Both relevant aortic valve stenosis (AS) and aortic valve insufficiency significantly contribute to structural changes in the ascending aorta (AA) and thus to its dilatation. In patients with severe AS undergoing transcatheter aortic valve replacement (TAVR), survival data regarding aortic changes and laboratory biomarker analyses are scarce. METHODS A total of 179 patients with severe AS and an available computed tomography were included in this retrospective study. AA was measured, and dilatation was defined as a diameter ≥ 40 mm. Thirty-two patients had dilatation of the AA. A further 32 patients from the present population with a normal AA were matched to the aortic dilatation group with respect to gender, age, body mass index and body surface area, and the resulting study groups were compared with each other. In addition to echocardiographic and clinical characteristics, the expression of cardiovascular biomarkers such as brain natriuretic peptide (BNP), soluble suppression of tumorigenicity-2 (sST2), growth/differentiation of factor-15 (GDF-15), heart-type fatty-acid binding protein (H-FABP), insulin-like growth factor binding protein 2 (IGF-BP2) and soluble urokinase-type plasminogen activator receptor (suPAR) was analyzed. Kaplan-Meier curves for short- and long-term survival were obtained, and Pearson's and Spearman's correlations were calculated to identify the predictors between the diameter of the AA and clinical parameters. RESULTS A total of 19% of the total cohort had dilatation of the AA. The study group with an AA diameter ≥ 40 mm showed a significantly low comorbidity with respect to diabetes mellitus in contrast to the comparison cohort with an AA diameter < 40 mm (p = 0.010). This result continued in the correlation analyses performed, as the presence of diabetes mellitus correlated negatively not only with the diameter of the AA (r = -0.404; p = 0.001) but also with the presence of aortic dilatation (r = -0.320; p = 0.010). In addition, the presence of AA dilatation after TAVR was shown to have no differences in terms of patient survival at 1, 3 and 5 years. There were no relevant differences in the cardiovascular biomarkers studied between the patients with dilated and normal AAs. CONCLUSION The presence of AA dilatation before successful TAVR was not associated with a survival disadvantage at the respective follow-up intervals of 1, 3 and 5 years. Diabetes mellitus in general seemed to have a protective effect against the development of AA dilatation or aneurysm in patients with severe AS.
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Affiliation(s)
- Elke Boxhammer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
- Correspondence: (E.B.); (S.H.); (B.S.)
| | - Stefan Hecht
- Department of Radiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
- Correspondence: (E.B.); (S.H.); (B.S.)
| | - Reinhard Kaufmann
- Department of Radiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
| | - Jürgen Kammler
- Department of Cardiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, 4020 Linz, Austria
| | - Jörg Kellermair
- Department of Cardiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, 4020 Linz, Austria
| | - Christian Reiter
- Department of Cardiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, 4020 Linz, Austria
| | - Kaveh Akbari
- Department of Radiology, Johannes Kepler University Hospital Linz, 4020 Linz, Austria
| | - Hermann Blessberger
- Department of Cardiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, 4020 Linz, Austria
| | - Clemens Steinwender
- Department of Cardiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, 4020 Linz, Austria
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
| | - Uta C. Hoppe
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
| | - Klaus Hergan
- Department of Radiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
| | - Bernhard Scharinger
- Department of Radiology, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
- Correspondence: (E.B.); (S.H.); (B.S.)
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13
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LOX-1 deficiency increases ruptured abdominal aortic aneurysm via thinning of adventitial collagen. Hypertens Res 2023; 46:63-74. [PMID: 36385349 DOI: 10.1038/s41440-022-01093-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 10/31/2022] [Indexed: 11/17/2022]
Abstract
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.
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14
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Daoud F, Arévalo Martínez M, Holst J, Holmberg J, Albinsson S, Swärd K. Role of smooth muscle YAP and TAZ in protection against phenotypic modulation, inflammation, and aneurysm development. Biochem Pharmacol 2022; 206:115307. [DOI: 10.1016/j.bcp.2022.115307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/12/2022] [Accepted: 10/12/2022] [Indexed: 11/02/2022]
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15
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Chen Y, Xu X, Wang L, Li K, Sun Y, Xiao L, Dai J, Huang M, Wang Y, Wang DW. Genetic insights into therapeutic targets for aortic aneurysms: A Mendelian randomization study. EBioMedicine 2022; 83:104199. [PMID: 35952493 PMCID: PMC9385553 DOI: 10.1016/j.ebiom.2022.104199] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/11/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND As aortic aneurysms (AAs) enlarge, they can become life-threatening if left undiagnosed or neglected. At present, there is a lack of radical treatments for preventing disease progression. Therefore, we aimed to identify effective drug targets that slow the progression of AAs. METHODS A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets which are associated with AAs. Summary statistics for AAs were obtained from two datasets: the UK Biobank (2228 cases and 408,565 controls) and the FinnGen study (3658 cases and 244,907 controls). Cis-expression quantitative trait loci (cis-eQTL) for druggable genes were retrieved from the eQTLGen Consortium and used as genetic instrumental variables. Colocalization analysis was performed to determine the probability that single nucleotide polymorphisms (SNPs) associated with AAs and eQTL shared causal genetic variants. FINDINGS Four drug targets (BTN3A1, FASN, PLAU, and PSMA4) showed significant MR results in two independent datasets. Proteasome 20S subunit alpha 4 (PSMA4) and plasminogen activator, urokinase (PLAU) in particular, were found to have strong evidence for colocalization with AAs, and abdominal aortic aneurysm in particular. Additionally, except for the association between PSMA4 and intracranial aneurysms, no association between genetically proxied inhibition of PLAU and PSMA4 was detected in increasing the risk of other cardiometabolic risks and diseases. INTERPRETATION This study supports that drug-targeting PLAU and PSMA4 inhibition may reduce the risk of AAs. FUNDING This work was supported by National Key R&D Program of China (NO. 2017YFC0909400), Nature Science Foundation of China (No. 91839302, 81790624), Project supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), and Tongji Hospital Clinical Research Flagship Program (no. 2019CR207).
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Affiliation(s)
- Yanghui Chen
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Xin Xu
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Linlin Wang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Ke Li
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Yang Sun
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Lei Xiao
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Jiaqi Dai
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Man Huang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Yan Wang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China; Department of Internal Medicine, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China.
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16
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Ren J, Wu L, Wu J, Tang X, Lv Y, Wang W, Li F, Yang D, Liu C, Zheng Y. The molecular mechanism of Ang II induced-AAA models based on proteomics analysis in ApoE -/- and CD57BL/6J mice. J Proteomics 2022; 268:104702. [PMID: 35988846 DOI: 10.1016/j.jprot.2022.104702] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 08/08/2022] [Accepted: 08/11/2022] [Indexed: 11/19/2022]
Abstract
Apolipoprotein knockout (ApoE-/-) and CD57BL/6J mouse models of angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) are commonly used in AAA research. However, the similarities and differences in the molecular mechanisms of AAA in these two genotypes have not been reported. In our study, we analyzed proteomics data from ApoE-/- and CD57BL/6J mouse models of Ang II-induced AAA and control mice by LC-MS/MS. Gene set enrichment analysis (GSEA) of differentially abundance proteins (DAPs) in the ApoE-/- or CD57BL/6J mouse groups was performed in R software, and infiltration of immune cells in groups was assessed. DAP that showed the same trend in abundance in ApoE-/- and CD57BL/6J mice (S-DAP) were identified and subjected to GO enrichment, KEGG pathway, and connectivity map (CMap) analyses. The protein-protein interaction (PPI) network of the S-DAP was drawn, the key S-DAP were identified by MCODE, and the transcription factors (TFs) of crucial S-DAP were predicted by iRegulon in Cytoscape. Male ApoE-/- and CD57BL/6J mouse models of Ang II-induced AAA are commonly used in AAA research, and extracellular matrix organization is associated with AAA in both of these models. However, there are some differences between the mechanisms underlying AAA in these two genotypes, and these differences need to be considered when studying AAA and selecting models. SIGNIFICANCE: Our research provided the first insight into the similarity and differential mechanisms of Ang II infused AAA models using ApoE-/- and CD57BL/6J mice. This study might provide the some advises for the selection of Ang II infused AAA models for further AAA researches.
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Affiliation(s)
- Jinrui Ren
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Vascular Surgery, State Key Laboratory of Complex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Lianglin Wu
- Department of Vascular Surgery, State Key Laboratory of Complex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jianqiang Wu
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyue Tang
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanze Lv
- Department of Vascular Surgery, State Key Laboratory of Complex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Wei Wang
- Department of Vascular Surgery, State Key Laboratory of Complex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Fangda Li
- Department of Vascular Surgery, State Key Laboratory of Complex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Dan Yang
- Department of Computational Biology and Bioinformatics, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changzheng Liu
- National Health Commission of the People's Republic of China (NHC), Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuehong Zheng
- Department of Vascular Surgery, State Key Laboratory of Complex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
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17
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Michel JB, Lagrange J, Regnault V, Lacolley P. Conductance Artery Wall Layers and Their Respective Roles in the Clearance Functions. Arterioscler Thromb Vasc Biol 2022; 42:e253-e272. [PMID: 35924557 DOI: 10.1161/atvbaha.122.317759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Evolutionary organization of the arterial wall into layers occurred concomitantly with the emergence of a highly muscularized, pressurized arterial system that facilitates outward hydraulic conductance and mass transport of soluble substances across the arterial wall. Although colliding circulating cells disperse potential energy within the arterial wall, the different layers counteract this effect: (1) the endothelium ensures a partial barrier function; (2) the media comprises smooth muscle cells capable of endocytosis/phagocytosis; (3) the outer adventitia and perivascular adipocytic tissue are the final receptacles of convected substances. While the endothelium forms a physical and a biochemical barrier, the medial layer is avascular, relying on the specific permeability properties of the endothelium for metabolic support. Different components of the media interact with convected molecules: medial smooth muscle cells take up numerous molecules via scavenger receptors and are capable of phagocytosis of macro/micro particles. The outer layers-the highly microvascularized innervated adventitia and perivascular adipose tissue-are also involved in the clearance functions of the media: the adventitia is the seat of immune response development, inward angiogenesis, macromolecular lymphatic drainage, and neuronal stimulation. Consequently, the clearance functions of the arterial wall are physiologically essential, but also may favor the development of arterial wall pathologies. This review describes how the walls of large conductance arteries have acquired physiological clearance functions, how this is determined by the attributes of the endothelial barrier, governed by endocytic and phagocytic capacities of smooth muscle cells, impacting adventitial functions, and the role of these clearance functions in arterial wall diseases.
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18
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Chao de la Barca JM, Richard A, Robert P, Eid M, Fouquet O, Tessier L, Wetterwald C, Faure J, Fassot C, Henrion D, Reynier P, Loufrani L. Metabolomic Profiling of Angiotensin-II-Induced Abdominal Aortic Aneurysm in Ldlr -/- Mice Points to Alteration of Nitric Oxide, Lipid, and Energy Metabolisms. Int J Mol Sci 2022; 23:ijms23126387. [PMID: 35742839 PMCID: PMC9223449 DOI: 10.3390/ijms23126387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/28/2022] [Accepted: 06/03/2022] [Indexed: 11/16/2022] Open
Abstract
Aneurysm is the second-most common disease affecting the aorta worldwide after atherosclerosis. While several clinical metabolomic studies have been reported, no study has reported deep metabolomic phenotyping in experimental animal models of aortic aneurysm. We performed a targeted metabolomics study on the blood and aortas of an experimental mice model of aortic aneurysm generated by high-cholesterol diet and angiotensin II in Ldlr−/− mice. The mice model showed a significant increase in media/lumen ratio and wall area, which is associated with lipid deposition within the adventitia, describing a hypertrophic remodeling with an aneurysm profile of the abdominal aorta. Altered aortas showed increased collagen remodeling, disruption of lipid metabolism, decreased glucose, nitric oxide and lysine metabolisms, and increased polyamines and asymmetric dimethylarginine (ADMA) production. In blood, a major hyperlipidemia was observed with decreased concentrations of glutamine, glycine, taurine, and carnitine, and increased concentrations of the branched amino acids (BCAA). The BCAA/glycine and BCAA/glutamine ratios discriminated with very good sensitivity and specificity between aneurysmatic and non-aneurysmatic mice. To conclude, our results reveal that experimental induction of aortic aneurysms causes a profound alteration in the metabolic profile in aortas and blood, mainly centered on an alteration of NO, lipid, and energetic metabolisms.
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Affiliation(s)
- Juan Manuel Chao de la Barca
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
- Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire (CHU), 49000 Angers, France; (L.T.); (C.W.); (J.F.)
| | - Alexis Richard
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
| | - Pauline Robert
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
| | - Maroua Eid
- Service de Chirurgie Cardiaque, Centre Hospitalier Universitaire (CHU), 49100 Angers, France; (M.E.); (O.F.)
| | - Olivier Fouquet
- Service de Chirurgie Cardiaque, Centre Hospitalier Universitaire (CHU), 49100 Angers, France; (M.E.); (O.F.)
| | - Lydie Tessier
- Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire (CHU), 49000 Angers, France; (L.T.); (C.W.); (J.F.)
| | - Céline Wetterwald
- Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire (CHU), 49000 Angers, France; (L.T.); (C.W.); (J.F.)
| | - Justine Faure
- Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire (CHU), 49000 Angers, France; (L.T.); (C.W.); (J.F.)
| | - Celine Fassot
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
| | - Daniel Henrion
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
- Angers University Hospital (CHU), 49100 Angers, France
| | - Pascal Reynier
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
- Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire (CHU), 49000 Angers, France; (L.T.); (C.W.); (J.F.)
| | - Laurent Loufrani
- UMR CNRS 6015—INSERM U1083, IRIS2, 3 rue Roger Amsler, 49100 Angers, France; (J.M.C.d.l.B.); (A.R.); (P.R.); (C.F.); (D.H.); (P.R.)
- INSERM U1083, 49100 Angers, France
- Mitovasc Institute, Université d’Angers, 49100 Angers, France
- Correspondence: ; Tel.: +33-244688263
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19
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Song H, Yang Y, Sun Y, Wei G, Zheng H, Chen Y, Cai D, Li C, Ma Y, Lin Z, Shi X, Liao W, Liao Y, Zhong L, Bin J. Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation. Mol Ther 2022; 30:915-931. [PMID: 34547461 PMCID: PMC8821928 DOI: 10.1016/j.ymthe.2021.09.017] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/09/2021] [Accepted: 09/14/2021] [Indexed: 02/04/2023] Open
Abstract
Macrophage polarization plays a crucial role in regulating abdominal aortic aneurysm (AAA) formation. Circular RNAs (circRNAs) are important regulators of macrophage polarization during the development of cardiovascular diseases. How-ever, the roles of circRNAs in regulating AAA formation through modulation of macrophage polarization remain unknown. In the present study, we compared circRNA microarray data under two distinct polarizing conditions (M1 and M2 macrophages) and identified an M1-enriched circRNA, circCdyl. Loss- and gain-of-function assay results demonstrated that circCdyl overexpression accelerated angiotensin II (Ang II)- and calcium chloride (CaCl2)-induced AAA formation by promoting M1 polarization and M1-type inflammation, while circCdyl deficiency showed the opposite effects. RNA pulldown, mass spectrometry analysis, and RNA immunoprecipitation (RIP) assays were conducted to elucidate the underlying mechanisms by which circCdyl regulates AAA formation and showed that circCdyl promotes vascular inflammation and M1 polarization by inhibiting interferon regulatory factor 4 (IRF4) entry into the nucleus, significantly inducing AAA formation. In addition, circCdyl was shown to act as a let-7c sponge, promoting C/EBP-δ expression in macrophages to induce M1 polarization. Our results indicate an important role for circCdyl-mediated macrophage polarization in AAA formation and provide a potent therapeutic target for AAA treatment.
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Affiliation(s)
- Haoyu Song
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Wards of Cadres, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, China
| | - Yang Yang
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Yili Sun
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Guoquan Wei
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Hao Zheng
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Yijin Chen
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Donghua Cai
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Chuling Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Yusheng Ma
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Zhongqiu Lin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Xiaoran Shi
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yulin Liao
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
| | - Lintao Zhong
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Department of Cardiology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, China,Corresponding author: Lintao Zhong, MD, PhD, Department of Cardiology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, China.
| | - Jianping Bin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China,Corresponding author: Jianping Bin, MD, PhD, Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, China.
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20
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Pilecki B, de Carvalho PVSD, Kirketerp-Møller KL, Schlosser A, Kejling K, Dubik M, Madsen NP, Stubbe J, Hansen PBL, Andersen TL, Moeller JB, Marcussen N, Azevedo V, Hvidsten S, Baun C, Shi GP, Lindholt JS, Sorensen GL. MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity. Front Cardiovasc Med 2021; 8:764337. [PMID: 34805319 PMCID: PMC8602692 DOI: 10.3389/fcvm.2021.764337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/15/2021] [Indexed: 01/14/2023] Open
Abstract
Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms. Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells. Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.
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Affiliation(s)
- Bartosz Pilecki
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Paulo V S D de Carvalho
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Department of General Biology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil.,Department of Mathematics and Informatics, University of Southern Denmark, Odense, Denmark
| | - Katrine L Kirketerp-Møller
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Anders Schlosser
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Karin Kejling
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Magdalena Dubik
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Nicklas P Madsen
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Jane Stubbe
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Pernille B L Hansen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Thomas L Andersen
- Department of Pathology, Odense University Hospital, Odense, Denmark.,Pathology Research Unit, Institute of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Jesper B Moeller
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
| | - Niels Marcussen
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Vasco Azevedo
- Department of General Biology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Svend Hvidsten
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | - Christina Baun
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | - Guo-Ping Shi
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Jes S Lindholt
- Department of Thoracic, Heart and Vascular Surgery, Odense University Hospital, Odense, Denmark
| | - Grith L Sorensen
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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Busch A, Bleichert S, Ibrahim N, Wortmann M, Eckstein HH, Brostjan C, Wagenhäuser MU, Goergen CJ, Maegdefessel L. Translating mouse models of abdominal aortic aneurysm to the translational needs of vascular surgery. JVS Vasc Sci 2021; 2:219-234. [PMID: 34778850 PMCID: PMC8577080 DOI: 10.1016/j.jvssci.2021.01.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 01/04/2021] [Indexed: 01/03/2023] Open
Abstract
Introduction Abdominal aortic aneurysm (AAA) is a condition that has considerable socioeconomic impact and an eventual rupture is associated with high mortality and morbidity. Despite decades of research, surgical repair remains the treatment of choice and no medical therapy is currently available. Animal models and, in particular, murine models, of AAA are a vital tool for experimental in vivo research. However, each of the different models has individual limitations and provide only partial mimicry of human disease. This narrative review addresses the translational potential of the available mouse models, highlighting unanswered questions from a clinical perspective. It is based on a thorough presentation of the available literature and more than a decade of personal experience, with most of the available models in experimental and translational AAA research. Results From all the models published, only the four inducible models, namely the angiotensin II model (AngII), the porcine pancreatic elastase perfusion model (PPE), the external periadventitial elastase application (ePPE), and the CaCl2 model have been widely used by different independent research groups. Although the angiotensin II model provides features of dissection and aneurysm formation, the PPE model shows reliable features of human AAA, especially beyond day 7 after induction, but remains technically challenging. The translational value of ePPE as a model and the combination with β-aminopropionitrile to induce rupture and intraluminal thrombus formation is promising, but warrants further mechanistic insights. Finally, the external CaCl2 application is known to produce inflammatory vascular wall thickening. Unmet translational research questions include the origin of AAA development, monitoring aneurysm growth, gender issues, and novel surgical therapies as well as novel nonsurgical therapies. Conclusion New imaging techniques, experimental therapeutic alternatives, and endovascular treatment options provide a plethora of research topics to strengthen the individual features of currently available mouse models, creating the possibility of shedding new light on translational research questions.
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Affiliation(s)
- Albert Busch
- Department for Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany.,Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), Berlin, Germany
| | - Sonja Bleichert
- Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Nahla Ibrahim
- Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Markus Wortmann
- Department of Vascular and Endovascular Surgery, Universitaetsklinik Heidelberg, Heidelberg, Germany
| | - Hans-Henning Eckstein
- Department for Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany
| | - Christine Brostjan
- Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Markus U Wagenhäuser
- Department of Vascular and Endovascular Surgery, Heinrich-Heine-University Medical Center Düsseldorf, Düsseldorf, Germany
| | - Craig J Goergen
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Ind
| | - Lars Maegdefessel
- Department for Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany.,Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), Berlin, Germany
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22
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Parvizi M, Franchi F, Arendt BK, Ebtehaj S, Rodriguez-Porcel M, Lanza IR. Senolytic agents lessen the severity of abdominal aortic aneurysm in aged mice. Exp Gerontol 2021; 151:111416. [PMID: 34022272 PMCID: PMC11443445 DOI: 10.1016/j.exger.2021.111416] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/16/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
Age is a major risk factor for abdominal aortic aneurysm (AAA), for which treatment options are limited to surgical intervention for large AAA and watchful waiting for small aneurysms. However, the factors that regulate the expansion of aneurysms are unclear. Development of new therapeutic strategies to prevent or treat small aneurysms awaits a more thorough understanding of the etiology of AAA formation and progression with aging. A variety of structural and functional changes have been reported in aging vasculature, but emerging evidence implicates senescent cells in the formation of AAA through their paracrine effects on vascular wall cell populations. Here we show that aging is associated with transcriptional changes in abdominal aortic tissue consistent with loss of smooth muscle cells, leukocyte adhesion, inflammation, and accumulation of senescent cells in the vascular wall and surrounding perivascular adipose tissue. Furthermore, aged mice demonstrated anatomical and histopathological features of AAA development in response to administration of angiotensin II over 28 days. Importantly, in our study we sought to determine if reducing senescent cells could lessen the severity of AAA in aged mice. We find that pretreatment of aged mice with oral senolytic agents (dasatinib + quercetin) reduced senescent cell abundance in the arterial walls and surrounding tissues and lessened the severity of AAA in response to angiotensin II administration. These data provide important preliminary evidence supporting a role of senescent cells in age-related AAA formation and progression and suggest that strategies to reduce senescent cell burden hold promise to lessen AAA severity.
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Affiliation(s)
- Mojtaba Parvizi
- Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Federico Franchi
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Bonnie K Arendt
- Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Sanam Ebtehaj
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America
| | | | - Ian R Lanza
- Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America.
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Lu W, Meng Z, Hernandez R, Zhou C. Fibroblast-specific IKKβ deficiency ameliorates angiotensin II-induced adverse cardiac remodeling in mice. JCI Insight 2021; 6:e150161. [PMID: 34324438 PMCID: PMC8492299 DOI: 10.1172/jci.insight.150161] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/28/2021] [Indexed: 12/03/2022] Open
Abstract
Cardiac inflammation and fibrosis contribute significantly to hypertension-related adverse cardiac remodeling. IκB kinase β (IKK-β), a central coordinator of inflammation through activation of NF-κB, has been demonstrated as a key molecular link between inflammation and cardiovascular disease. However, the cell-specific contribution of IKK-β signaling toward adverse cardiac remodeling remains elusive. Cardiac fibroblasts are one of the most populous nonmyocyte cell types in the heart that play a key role in mediating cardiac fibrosis and remodeling. To investigate the function of fibroblast IKK-β, we generated inducible fibroblast-specific IKK-β–deficient mice. Here, we report an important role of IKK-β in the regulation of fibroblast functions and cardiac remodeling. Fibroblast-specific IKK-β–deficient male mice were protected from angiotensin II–induced cardiac hypertrophy, fibrosis, and macrophage infiltration. Ablation of fibroblast IKK-β inhibited angiotensin II–stimulated fibroblast proinflammatory and profibrogenic responses, leading to ameliorated cardiac remodeling and improved cardiac function in IKK-β–deficient mice. Findings from this study establish fibroblast IKK-β as a key factor regulating cardiac fibrosis and function in hypertension-related cardiac remodeling.
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Affiliation(s)
- Weiwei Lu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States of America
| | - Zhaojie Meng
- Division of Biomedical Sciences, University of California, Riverside, United States of America
| | - Rebecca Hernandez
- Division of Biomedical Sciences, University of California, Riverside, United States of America
| | - Changcheng Zhou
- Division of Biomedical Sciences, University of California, Riverside, United States of America
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24
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Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimoto K, Ishida T, Morishita S, Komatsu N, Ikeda K, Takeishi Y. Crucial role of hematopoietic JAK2 V617F in the development of aortic aneurysms. Haematologica 2021; 106:1910-1922. [PMID: 33567809 PMCID: PMC8252954 DOI: 10.3324/haematol.2020.264085] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Indexed: 12/11/2022] Open
Abstract
JAK2 V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPN) and is associated with vascular complications. However, the impact of hematopoietic JAK2 V617F on aortic aneurysms (AA) remains unknown. Our cross-sectional study indicated that nine (23%) of 39 MPN patients with JAK2 V617F exhibited the presence of AA. In order to clarify whether the hematopoietic JAK2 V617F contributes to the AA, we applied bone marrow transplantation (BMT) with the donor cells from Jak2 V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in the JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2 V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2 V617F in the abdominal aorta was confirmed by use of the reporter green fluorescent proteintransgene. BM-derived macrophages carrying JAK2 V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AA in MPN with JAK2 V617F.
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Affiliation(s)
- Tetsuro Yokokawa
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan; Department of Pulmonary Hypertension, Fukushima Medical University, Fukushima
| | - Tomofumi Misaka
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan; Department of Advanced Cardiac Therapeutics, Fukushima Medical University, Fukushima.
| | - Yusuke Kimishima
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima
| | - Kento Wada
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima
| | - Keiji Minakawa
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima
| | - Koichi Sugimoto
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan; Department of Pulmonary Hypertension, Fukushima Medical University, Fukushima
| | - Takafumi Ishida
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima
| | - Soji Morishita
- Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo
| | - Norio Komatsu
- Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo
| | - Kazuhiko Ikeda
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima.
| | - Yasuchika Takeishi
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima
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25
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Current pharmacological management of aortic aneurysm. J Cardiovasc Pharmacol 2021; 78:211-220. [PMID: 33990514 DOI: 10.1097/fjc.0000000000001054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/23/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Aortic aneurysm (AA) remains one of the primary causes of death worldwide. Of the major treatments, prophylactic operative repair is used for AA to avoid potential aortic dissection (AD) or rupture. To halt the development of AA and alleviate its progression into AD, pharmacological treatment has been investigated for years. Currently, β-adrenergic blocking agents, losartan, irbesartan, angiotensin-converting-enzyme inhibitors, statins, antiplatelet agents, doxycycline, and metformin have been investigated as potential candidates for preventing AA progression. However, the paradox between preclinical successes and clinical failures still exists, with no medical therapy currently available for ideally negating the disease progression. This review describes the current drugs used for pharmacological management of AA and their individual potential mechanisms. Preclinical models for drug screening and evaluation are also discussed to gain a better understanding of the underlying pathophysiology and ultimately find new therapeutic targets for AA.
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26
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Bäck M, Michel JB. From organic and inorganic phosphates to valvular and vascular calcifications. Cardiovasc Res 2021; 117:2016-2029. [PMID: 33576771 PMCID: PMC8318101 DOI: 10.1093/cvr/cvab038] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/26/2020] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Calcification of the arterial wall and valves is an important part of the pathophysiological process of peripheral and coronary atherosclerosis, aortic stenosis, ageing, diabetes, and chronic kidney disease. This review aims to better understand how extracellular phosphates and their ability to be retained as calcium phosphates on the extracellular matrix initiate the mineralization process of arteries and valves. In this context, the physiological process of bone mineralization remains a human model for pathological soft tissue mineralization. Soluble (ionized) calcium precipitation occurs on extracellular phosphates; either with inorganic or on exposed organic phosphates. Organic phosphates are classified as either structural (phospholipids, nucleic acids) or energetic (corresponding to phosphoryl transfer activities). Extracellular phosphates promote a phenotypic shift in vascular smooth muscle and valvular interstitial cells towards an osteoblast gene expression pattern, which provokes the active phase of mineralization. A line of defense systems protects arterial and valvular tissue calcifications. Given the major roles of phosphate in soft tissue calcification, phosphate mimetics, and/or prevention of phosphate dissipation represent novel potential therapeutic approaches for arterial and valvular calcification.
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Affiliation(s)
- Magnus Bäck
- Division of Valvular and Coronary Disease, Department of Cardiology, Karolinska University Hospital, 141 86 Stockholm, Sweden.,Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,University of Lorraine, Nancy University Hospital, INSERM U1116, Nancy, France
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27
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Kopacz A, Klóska D, Werner E, Hajduk K, Grochot-Przęczek A, Józkowicz A, Piechota-Polańczyk A. A Dual Role of Heme Oxygenase-1 in Angiotensin II-Induced Abdominal Aortic Aneurysm in the Normolipidemic Mice. Cells 2021; 10:cells10010163. [PMID: 33467682 PMCID: PMC7830394 DOI: 10.3390/cells10010163] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 11/16/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) bears a high risk of rupture and sudden death of the patient. The pathogenic mechanisms of AAA remain elusive, and surgical intervention represents the only treatment option. Heme oxygenase-1 (HO-1), a heme degrading enzyme, is induced in AAA, both in mice and humans. HO-1 was reported to mitigate AAA development in an angiotensin II (AngII)-induced model of AAA in hyperlipidemic ApoE-/- mice. Since the role of hyperlipidaemia in the pathogenesis of AAA remains controversial, we aimed to evaluate the significance of HO-1 in the development and progression of AAA in normolipidemic animals. The experiments were performed in HO-1-deficient mice and their wild-type counterparts. We demonstrated in non-hypercholesterolemic mice that the high-dose of AngII leads to the efficient formation of AAA, which is attenuated by HO-1 deficiency. Yet, if formed, they are significantly more prone to rupture upon HO-1 shortage. Differential susceptibility to AAA formation does not rely on enhanced inflammatory response or oxidative stress. AAA-resistant mice are characterized by an increase in regulators of aortic remodeling and angiotensin receptor-2 expression, significant medial thickening, and delayed blood pressure elevation in response to AngII. To conclude, we unveil a dual role of HO-1 deficiency in AAA in normolipidemic mice, where it protects against AAA development, but exacerbates the state of formed AAA.
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Affiliation(s)
- Aleksandra Kopacz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
| | - Damian Klóska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
| | - Ewa Werner
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
- Department of Animal Reproduction, Anatomy and Genomic, Faculty of Animal Science, University of Agriculture, 30-059 Krakow, Poland
| | - Karolina Hajduk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
| | - Anna Grochot-Przęczek
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
| | - Aleksandra Piechota-Polańczyk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-392 Krakow, Poland; (A.K.); (D.K.); (E.W.); (K.H.); (A.G.-P.); (A.J.)
- Correspondence:
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28
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Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture. Int J Mol Sci 2020; 21:ijms21197250. [PMID: 33008131 PMCID: PMC7583758 DOI: 10.3390/ijms21197250] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/19/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results.
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29
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Lu H, Sun J, Liang W, Chang Z, Rom O, Zhao Y, Zhao G, Xiong W, Wang H, Zhu T, Guo Y, Chang L, Garcia-Barrio MT, Zhang J, Chen YE, Fan Y. Cyclodextrin Prevents Abdominal Aortic Aneurysm via Activation of Vascular Smooth Muscle Cell Transcription Factor EB. Circulation 2020; 142:483-498. [PMID: 32354235 DOI: 10.1161/circulationaha.119.044803] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA. METHODS The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Using VSMC-selective Tfeb knockout mice and different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator in AAA in vivo. RESULTS We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs, and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2. B-cell lymphoma 2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. We consistently observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-β-cyclodextrin, a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Last, we found that 2-hydroxypropyl-β-cyclodextrin inhibits AAA in a VSMC TFEB-dependent manner in mouse models. CONCLUSIONS Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by 2-hydroxypropyl-β-cyclodextrin may be a promising therapeutic strategy for the prevention and treatment of AAA.
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Affiliation(s)
- Haocheng Lu
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Jinjian Sun
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Wenying Liang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Ziyi Chang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Oren Rom
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Yang Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Guizhen Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Wenhao Xiong
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Huilun Wang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Tianqing Zhu
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Yanhong Guo
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Lin Chang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Minerva T Garcia-Barrio
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Jifeng Zhang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
| | - Y Eugene Chen
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor
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30
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Yao Y, Cheng K, Cheng Z. Evaluation of a smart activatable MRI nanoprobe to target matrix metalloproteinases in the early-stages of abdominal aortic aneurysms. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 26:102177. [PMID: 32142755 DOI: 10.1016/j.nano.2020.102177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 01/14/2020] [Accepted: 02/23/2020] [Indexed: 10/24/2022]
Abstract
Matrix metalloproteinases (MMPs) activation contributes to abdominal aortic aneurysm (AAA) growth and rupture. The study was to evaluate the ability of a novel activatable magnetic resonance imaging (MRI) nanoprobe, to target MMPs in an Angiotensin II (ANG II)-induced AAA model. The activatable nanoprobe is composed of a hydrophilic polyethylene glycol coating layer immobilized on the external surface of core/shell Fe/iron oxide nanoparticles; between them, there was grafted the MMP peptide substrate. In the ANG II infusion mice model of AAAs, MRI was performed to characterize the progression of model. The contrast-to-noise ratio was lower in the aneurysm of the mice injected with activatable nanoprobe. Histological studies revealed the presence of MMPs and iron-oxide in regions of MR signal decrease. MRI combined with nanoprobe allows the detection of MMP activity within the wall of AAA, thus representing a potential noninvasive method to predict the rupture risk of AAA.
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Affiliation(s)
- Yuyu Yao
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, China; Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Kai Cheng
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Zhen Cheng
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, USA.
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31
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Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection. Pharmaceuticals (Basel) 2019; 12:ph12030118. [PMID: 31390798 PMCID: PMC6789891 DOI: 10.3390/ph12030118] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/25/2019] [Accepted: 08/02/2019] [Indexed: 12/12/2022] Open
Abstract
Abdominal Aortic Aneurysm (AAA) affects 4–5% of men over 65, and Aortic Dissection (AD) is a life-threatening aortic pathology associated with high morbidity and mortality. Initiators of AAA and AD include smoking and arterial hypertension, whilst key pathophysiological features of AAA and AD include chronic inflammation, hypoxia, and large modifications to the extra cellular matrix (ECM). As it stands, only surgical methods are available for preventing aortic rupture in patients, which often presents difficulties for recovery. No pharmacological treatment is available, as such researchers are attempting to understand the cellular and molecular pathophysiology of AAA and AD. Upregulation of matrix metalloproteinase (MMPs), particularly MMP-2 and MMP-9, has been identified as a key event occurring during aneurysmal growth. As such, several animal models of AAA and AD have been used to investigate the therapeutic potential of suppressing MMP-2 and MMP-9 activity as well as modulating the activity of other MMPs, and TIMPs involved in the pathology. Whilst several studies have offered promising results, targeted delivery of MMP inhibition still needs to be developed in order to avoid surgery in high risk patients.
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32
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Abstract
Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic aneurysm identified hundreds of candidate strategies for stabilization, and data from preoperative clinical intervention studies show that interventions in the pathways of the activated inflammatory and proteolytic cascades in enlarging abdominal aortic aneurysm are feasible. Similarly, the concept of pharmaceutical aorta stabilization in Marfan syndrome is supported by a wealth of promising studies in the murine models of Marfan syndrome-related aortapathy. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and aortic root stabilization in Marfan syndrome, these claims are not consistently confirmed in larger and controlled studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models of aneurysm disease and perhaps incomplete understanding of the pathological processes involved in later stages of aortic aneurysm progression. Preclinical models more reflective of human pathophysiology, identification of biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance the opportunities in this important field.
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Affiliation(s)
- Jan H. Lindeman
- Dept. Vascular Surgery, Leiden University Medical Center, The Netherlands
| | - Jon S. Matsumura
- Division of Vascular Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
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Cameron SJ, Russell HM, Owens AP. Antithrombotic therapy in abdominal aortic aneurysm: beneficial or detrimental? Blood 2018; 132:2619-2628. [PMID: 30228233 PMCID: PMC6302498 DOI: 10.1182/blood-2017-08-743237] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 09/10/2018] [Indexed: 12/13/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150 000 new cases and nearly 15 000 deaths annually, the only approved treatment of AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. Because most clinically relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression. However, the efficacy of these treatments has not been shown, and the effects of shrinking the ILT may be as detrimental as they are beneficial. This review discusses the prospect of anticoagulant and antiplatelet (termed collectively as antithrombotic) therapies in AAA. Herein, we discuss the role of the coagulation cascade and platelet activation in human and animal models of AAA, the composition of ILT in AAA, a possible role of the ILT in aneurysm stabilization, and the implications of antithrombotic drugs in AAA treatment.
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Affiliation(s)
- Scott J Cameron
- Department of Medicine (Cardiology) and
- Department of Surgery (Cardiac Surgery), University of Rochester School of Medicine, Rochester, NY; and
| | - Hannah M Russell
- Division of Cardiovascular Health and Disease and
- Pathobiology and Molecular Medicine, Department of Internal Medicine, The University of Cincinnati College of Medicine, Cincinnati, OH
| | - A Phillip Owens
- Division of Cardiovascular Health and Disease and
- Pathobiology and Molecular Medicine, Department of Internal Medicine, The University of Cincinnati College of Medicine, Cincinnati, OH
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Nitsa A, Toutouza M, Machairas N, Mariolis A, Philippou A, Koutsilieris M. Vitamin D in Cardiovascular Disease. In Vivo 2018; 32:977-981. [PMID: 30150419 DOI: 10.21873/invivo.11338] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 06/12/2018] [Accepted: 06/18/2018] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease is the prevalent cause of morbidity and mortality in the world, affecting many millions of individuals every year. Atherosclerosis, a chronic inflammatory condition that involves different cell types, several cytokines and adhesion molecules, is the underlying cause of cardiovascular disease. Vitamin D is known to control skeletal patho/physiology, regulating calcium and phosphorus and bone remodeling along with other calcium-regulating hormones. However, several active metabolites of vitamin D can exert both direct action, mainly via vitamin D3 receptor trans-activation and indirect actions on several other tissues by an endocrine, autocrine and paracrine manners. With regard to cardiovascular disease, vitamin D deficiency has been associated with activation of the pro-inflammatory mechanism, promoting atherogenesis. There are several large-scale clinical studies, as well as meta-analyses that support this finding. However, it is still unclear whether the plasma 25-hydroxyvitamin D level can be used as a biomarker for future cardiovascular disease. Herein we review the studies reporting a causative role for vitamin D in cardiovascular disease.
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Affiliation(s)
- Alkippi Nitsa
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Biochemistry & Microbiology Laboratory, Hipokrateion Hospital, Athens, Greece
| | - Marina Toutouza
- Biochemistry & Microbiology Laboratory, Hipokrateion Hospital, Athens, Greece
| | - Nikolaos Machairas
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Anastassios Philippou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Portier I, Martinod K, Desender L, Vandeputte N, Deckmyn H, Vanhoorelbeke K, De Meyer SF. von Willebrand factor deficiency does not influence angiotensin II-induced abdominal aortic aneurysm formation in mice. Sci Rep 2018; 8:16645. [PMID: 30413751 PMCID: PMC6226453 DOI: 10.1038/s41598-018-35029-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 10/15/2018] [Indexed: 12/14/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) refers to a localized dilation of the abdominal aorta that exceeds the normal diameter by 50%. AAA pathophysiology is characterized by progressive inflammation, vessel wall destabilization and thrombus formation. Our aim was to investigate the potential involvement of von Willebrand factor (VWF), a thrombo-inflammatory plasma protein, in AAA pathophysiology using a dissection-based and angiotensin II infusion-induced AAA mouse model. AAA formation was induced in both wild-type and VWF-deficient mice by subcutaneous implantation of an osmotic pump, continuously releasing 1000 ng/kg/min angiotensin II. Survival was monitored, but no significant difference was observed between both groups. After 28 days, the suprarenal aortic segment of the surviving mice was harvested. Both AAA incidence and severity were similar in wild-type and VWF-deficient mice, indicating that AAA formation was not significantly influenced by the absence of VWF. Although VWF plasma levels increased after the infusion period, these increases were not correlated with AAA progression. Also detailed histological analyses of important AAA hallmarks, including elastic degradation, intramural thrombus formation and leukocyte infiltration, did not reveal differences between both groups. These data suggest that, at least in the angiotensin II infusion-induced AAA mouse model, the role of VWF in AAA pathophysiology is limited.
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Affiliation(s)
- Irina Portier
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Kimberly Martinod
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Linda Desender
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Nele Vandeputte
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Hans Deckmyn
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Karen Vanhoorelbeke
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Simon F De Meyer
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
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Wu Y, Su SA, Xie Y, Shen J, Zhu W, Xiang M. Murine models of vascular endothelial injury: Techniques and pathophysiology. Thromb Res 2018; 169:64-72. [PMID: 30015230 DOI: 10.1016/j.thromres.2018.07.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 06/08/2018] [Accepted: 07/08/2018] [Indexed: 12/13/2022]
Abstract
Vascular endothelial injury (VEI) triggers pathological processes in various cardiovascular diseases, such as coronary heart disease and hypertension. To further elucidate the in vivo pathological mechanisms of VEI, many animal models have been established. For the easiness of genetic manipulation and feeding, murine models become most commonly applied for investigating VEI. Subsequently, countless valuable information concerning pathogenesis has been obtained and therapeutic strategies for VEI have been developed. This review will highlight some typical murine VEI models from the perspectives of pharmacological intervention, surgery and genetic manipulation. The techniques, pathophysiology, advantages, disadvantages and the experimental purpose of each model will also be discussed.
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Affiliation(s)
- Yue Wu
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Sheng-An Su
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Yao Xie
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Jian Shen
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Wei Zhu
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China.
| | - Meixiang Xiang
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China.
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Carino D, Sarac TP, Ziganshin BA, Elefteriades JA. Abdominal Aortic Aneurysm: Evolving Controversies and Uncertainties. Int J Angiol 2018; 27:58-80. [PMID: 29896039 PMCID: PMC5995687 DOI: 10.1055/s-0038-1657771] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is defined as a permanent dilatation of the abdominal aorta that exceeds 3 cm. Most AAAs arise in the portion of abdominal aorta distal to the renal arteries and are defined as infrarenal. Most AAAs are totally asymptomatic until catastrophic rupture. The strongest predictor of AAA rupture is the diameter. Surgery is indicated to prevent rupture when the risk of rupture exceeds the risk of surgery. In this review, we aim to analyze this disease comprehensively, starting from an epidemiological perspective, exploring etiology and pathophysiology, and concluding with surgical controversies. We will pursue these goals by addressing eight specific questions regarding AAA: (1) Is the incidence of AAA increasing? (2) Are ultrasound screening programs for AAA effective? (3) What causes AAA: Genes versus environment? (4) Animal models: Are they really relevant? (5) What pathophysiology leads to AAA? (6) Indications for AAA surgery: Are surgeons over-eager to operate? (7) Elective AAA repair: Open or endovascular? (8) Emergency AAA repair: Open or endovascular?
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Affiliation(s)
- Davide Carino
- Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
| | - Timur P. Sarac
- Section of Vascular and Endovascular Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
| | - Bulat A. Ziganshin
- Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
- Department of Surgical Diseases # 2, Kazan State Medical University, Kazan, Russia
| | - John A. Elefteriades
- Aortic Institute at Yale-New Haven, Yale University School of Medicine, New Haven, Connecticut
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Rossignoli A, Vorkapic E, Wanhainen A, Länne T, Skogberg J, Folestad E, Wågsäter D. Plasma cholesterol lowering in an AngII‑infused atherosclerotic mouse model with moderate hypercholesterolemia. Int J Mol Med 2018; 42:471-478. [PMID: 29658561 DOI: 10.3892/ijmm.2018.3619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 02/22/2018] [Indexed: 11/06/2022] Open
Abstract
Atherosclerosis is the main underlying causes of cardiovascular disease. There is a well‑established association between high blood cholesterol levels and the extent of atherosclerosis. Furthermore, atherosclerosis has been proposed to augment abdominal aortic aneurysm (AAA) formation. As patients with AAA often have parallel atherosclerotic disease and are therefore often on cholesterol‑lowering therapy, it is not possible to fully address the independent effects of plasma cholesterol lowering (PCL) treatment on AAA. The present study investigated the effect of angiotensin II (AngII)‑infusion in modestly hypercholesterolemic Ldlr‑/‑Apob100/100Mttpflox/floxMx1‑Cre mice with or without PCL treatment on a morphological and molecular level, in terms of atherosclerosis and AAA development. AngII infusion in the study mice resulted in an increased atherosclerotic lesion area and increased infiltration of inflammatory leukocytes, which was not observed in mice with PCL induced prior to AngII infusion. This suggested that AngII infusion in this mouse model induced atherosclerosis development, and that plasma cholesterol levels represent a controlling factor. Furthermore, AngII infusion in Ldlr‑/‑Apob100/100Mttpflox/floxMx1‑Cre mice caused a modest aneurysmal phenotype, and no differences in AAA development were observed between the different study groups. However, the fact that modest hypercholesterolemic mice did not develop AAA in a classical aneurysmal model indicated that plasma cholesterol levels are important for disease development.
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Affiliation(s)
- Aránzazu Rossignoli
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Emina Vorkapic
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, 58183 Linköping, Sweden
| | - Anders Wanhainen
- Department of Surgical Sciences, Section of Vascular Surgery, Uppsala University, 75185 Uppsala, Sweden
| | - Toste Länne
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, 58183 Linköping, Sweden
| | - Josefin Skogberg
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Erika Folestad
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Dick Wågsäter
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, 58183 Linköping, Sweden
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Zhao G, Fu Y, Cai Z, Yu F, Gong Z, Dai R, Hu Y, Zeng L, Xu Q, Kong W. Unspliced XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction. Circ Res 2017; 121:1331-1345. [PMID: 29089350 DOI: 10.1161/circresaha.117.311450] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 10/26/2017] [Accepted: 10/30/2017] [Indexed: 11/16/2022]
Abstract
RATIONALE Although not fully understood, the phenotypic transition of vascular smooth muscle cells exhibits at the early onset of the pathology of aortic aneurysms. Exploring the key regulators that are responsible for maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) may confer vascular homeostasis and prevent aneurysmal disease. XBP1 (X-box binding protein 1), which exists in a transcriptionally inactive unspliced form (XBP1u) and a spliced active form (XBP1s), is a key component in response to endoplasmic reticular stress. Compared with XBP1s, little is known about the role of XBP1u in vascular homeostasis and disease. OBJECTIVE We aim to investigate the role of XBP1u in VSMC phenotypic switching and the pathogenesis of aortic aneurysms. METHODS AND RESULTS XBP1u, but not XBP1s, was markedly repressed in the aorta during the early onset of aortic aneurysm in both angiotensin II-infused apolipoprotein E knockout (ApoE-/-) and CaPO4 (calcium phosphate)-induced C57BL/6J murine models, in parallel with a decrease in smooth muscle cell contractile apparatus proteins. In vivo studies revealed that XBP1 deficiency in smooth muscle cells caused VSMC dedifferentiation, enhanced vascular inflammation and proteolytic activity, and significantly aggravated both thoracic and abdominal aortic aneurysms in mice. XBP1 deficiency, but not an inhibition of XBP1 splicing, induced VSMC switching from the contractile phenotype to a proinflammatory and proteolytic phenotype. Mechanically, in the cytoplasm, XBP1u directly associated with the N terminus of FoxO4 (Forkhead box protein O 4), a recognized repressor of VSMC differentiation via the interaction and inhibition of myocardin. Blocking the XBP1u-FoxO4 interaction facilitated nuclear translocation of FoxO4, repressed smooth muscle cell marker genes expression, promoted proinflammatory and proteolytic phenotypic transitioning in vitro, and stimulated aortic aneurysm formation in vivo. CONCLUSIONS Our study revealed the pivotal role of the XBP1u-FoxO4-myocardin axis in maintaining the VSMC contractile phenotype and providing protection from aortic aneurysm formation.
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Affiliation(s)
- Guizhen Zhao
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Yi Fu
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Zeyu Cai
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Fang Yu
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Ze Gong
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Rongbo Dai
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Yanhua Hu
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Lingfang Zeng
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Qingbo Xu
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.)
| | - Wei Kong
- From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (G.Z., Y.F., Z.C., F.Y., Z.G., R.D., W.K.); and BHF Centre, School of Cardiovascular Medicine & Science, King's College London, United Kingdom (Y.H., L.Z., Q.X.).
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MESH Headings
- Animals
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/pathology
- Aorta, Abdominal/physiopathology
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Aorta, Thoracic/physiopathology
- Aortic Aneurysm, Abdominal/epidemiology
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/pathology
- Aortic Aneurysm, Abdominal/physiopathology
- Aortic Aneurysm, Thoracic/epidemiology
- Aortic Aneurysm, Thoracic/metabolism
- Aortic Aneurysm, Thoracic/pathology
- Aortic Aneurysm, Thoracic/physiopathology
- Disease Models, Animal
- Humans
- Risk Factors
- Signal Transduction
- Vascular Remodeling
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Affiliation(s)
- Hong Lu
- From the Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, Lexington.
| | - Alan Daugherty
- From the Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, Lexington
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Shen YH, LeMaire SA. Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections. Curr Probl Surg 2017; 54:95-155. [PMID: 28521856 DOI: 10.1067/j.cpsurg.2017.01.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 01/16/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Ying H Shen
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX.
| | - Scott A LeMaire
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.
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Animal Models Used to Explore Abdominal Aortic Aneurysms: A Systematic Review. Eur J Vasc Endovasc Surg 2016; 52:487-499. [DOI: 10.1016/j.ejvs.2016.07.004] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 07/01/2016] [Indexed: 01/09/2023]
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Lu H, Howatt DA, Balakrishnan A, Graham MJ, Mullick AE, Daugherty A. Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II-Induced Abdominal Aortic Aneurysms in C57BL/6 Mice-Brief Report. Arterioscler Thromb Vasc Biol 2016; 36:1753-7. [PMID: 27470509 DOI: 10.1161/atvbaha.116.307613] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 06/17/2016] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Gain-of-function mutations of PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral (AAV) vector expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms. APPROACH AND RESULTS In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y). AAV at 3 doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose dependently in mice injected with AAV containing PCSK9D377Y mutation and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein receptor(-/-) mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent abdominal aortic aneurysmal formation, compared to low-density lipoprotein receptor(-/-) mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male low-density lipoprotein receptor(-/-) mice did not influence AngII-induced abdominal aortic aneurysms. CONCLUSION AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting abdominal aortic aneurysms in C57BL/6 mice infused with AngII.
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Affiliation(s)
- Hong Lu
- From the Department of Physiology (H.L., A.D.), Saha Cardiovascular Research Center (H.L., D.A.H., A.B., A.D.), University of Kentucky, Lexington; and Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA (M.J.G., A.E.M.).
| | - Deborah A Howatt
- From the Department of Physiology (H.L., A.D.), Saha Cardiovascular Research Center (H.L., D.A.H., A.B., A.D.), University of Kentucky, Lexington; and Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA (M.J.G., A.E.M.)
| | - Anju Balakrishnan
- From the Department of Physiology (H.L., A.D.), Saha Cardiovascular Research Center (H.L., D.A.H., A.B., A.D.), University of Kentucky, Lexington; and Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA (M.J.G., A.E.M.)
| | - Mark J Graham
- From the Department of Physiology (H.L., A.D.), Saha Cardiovascular Research Center (H.L., D.A.H., A.B., A.D.), University of Kentucky, Lexington; and Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA (M.J.G., A.E.M.)
| | - Adam E Mullick
- From the Department of Physiology (H.L., A.D.), Saha Cardiovascular Research Center (H.L., D.A.H., A.B., A.D.), University of Kentucky, Lexington; and Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA (M.J.G., A.E.M.)
| | - Alan Daugherty
- From the Department of Physiology (H.L., A.D.), Saha Cardiovascular Research Center (H.L., D.A.H., A.B., A.D.), University of Kentucky, Lexington; and Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA (M.J.G., A.E.M.).
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Ragot H, Monfort A, Baudet M, Azibani F, Fazal L, Merval R, Polidano E, Cohen-Solal A, Delcayre C, Vodovar N, Chatziantoniou C, Samuel JL. Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension. Hypertension 2016; 68:392-400. [PMID: 27296994 DOI: 10.1161/hypertensionaha.116.07694] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 05/10/2016] [Indexed: 12/28/2022]
Abstract
Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell-specific conditional RBPJκ knockout. At baseline, both genotypes exhibited a cardiac arteriolar rarefaction associated with oxidative stress. In response to angiotensin II-induced hypertension, the heart of Notch3 knockout and SM-RBPJκ knockout mice did not adapt to pressure overload and developed heart failure, which could lead to an early and fatal acute decompensation of heart failure. This cardiac maladaptation was characterized by an absence of media hypertrophy of the media arteries, the transition of smooth muscle cells toward a synthetic phenotype, and an alteration of angiogenic pathways. A subset of mice exhibited an early fatal acute decompensated heart failure, in which the same alterations were observed, although in a more rapid timeframe. Altogether, these observations indicate that Notch3 plays a major role in coronary adaptation to pressure overload. These data also show that the hypertrophy of coronary arterial media on pressure overload is mandatory to initially maintain a normal cardiac function and is regulated by the Notch3/RBPJκ pathway.
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Affiliation(s)
- Hélène Ragot
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Astrid Monfort
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Mathilde Baudet
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Fériel Azibani
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Loubina Fazal
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Régine Merval
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Evelyne Polidano
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Alain Cohen-Solal
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Claude Delcayre
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Nicolas Vodovar
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Christos Chatziantoniou
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.)
| | - Jane-Lise Samuel
- From the Inserm UMR-S 942 and Paris Diderot University, Paris, France (H.R., A.M., M.B., F.A., L.F., R.M., E.P., A.C.-S., C.D., N.V., J.-L.S.); Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S.); and Inserm UMR-S 1155 and Pierre and Marie Curie University, Paris, France (C.C.).
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Tai HC, Tsai PJ, Chen JY, Lai CH, Wang KC, Teng SH, Lin SC, Chang AYW, Jiang MJ, Li YH, Wu HL, Maeda N, Tsai YS. Peroxisome Proliferator-Activated Receptor γ Level Contributes to Structural Integrity and Component Production of Elastic Fibers in the Aorta. Hypertension 2016; 67:1298-308. [PMID: 27045031 DOI: 10.1161/hypertensionaha.116.07367] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 03/09/2016] [Indexed: 01/24/2023]
Abstract
Loss of integrity and massive disruption of elastic fibers are key features of abdominal aortic aneurysm (AAA). Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to attenuate AAA through inhibition of inflammation and proteolytic degradation. However, its involvement in elastogenesis during AAA remains unclear. PPARγ was highly expressed in human AAA within all vascular cells, including inflammatory cells and fibroblasts. In the aortas of transgenic mice expressing PPARγ at 25% normal levels (Pparg(C) (/-) mice), we observed the fragmentation of elastic fibers and reduced expression of vital elastic fiber components of elastin and fibulin-5. These were not observed in mice with 50% normal PPARγ expression (Pparg(+/-) mice). Infusion of a moderate dose of angiotensin II (500 ng/kg per minute) did not induce AAA but Pparg(+/-) aorta developed flattened elastic lamellae, whereas Pparg(C/-) aorta showed severe destruction of elastic fibers. After infusion of angiotensin II at 1000 ng/kg per minute, 73% of Pparg(C/-) mice developed atypical suprarenal aortic aneurysms: superior mesenteric arteries were dilated with extensive collagen deposition in adventitia and infiltrations of inflammatory cells. Although matrix metalloproteinase inhibition by doxycycline somewhat attenuated the dilation of aneurysm, it did not reduce the incidence nor elastic lamella deterioration in angiotensin II-infused Pparg(C/-) mice. Furthermore, PPARγ antagonism downregulated elastin and fibulin-5 in fibroblasts, but not in vascular smooth muscle cells. Chromatin immunoprecipitation assay demonstrated PPARγ binding in the genomic sequence of fibulin-5 in fibroblasts. Our results underscore the importance of PPARγ in AAA development though orchestrating proper elastogenesis and preserving elastic fiber integrity.
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Affiliation(s)
- Haw-Chih Tai
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Pei-Jane Tsai
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Ju-Yi Chen
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Chao-Han Lai
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Kuan-Chieh Wang
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Shih-Hua Teng
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Shih-Chieh Lin
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Alice Y W Chang
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Meei-Jyh Jiang
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Yi-Heng Li
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Hua-Lin Wu
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Nobuyo Maeda
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.)
| | - Yau-Sheng Tsai
- From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
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Kaźmierski P, Pająk M, Bogusiak K. Concomitance of atherosclerotic lesions in arteries of the lower extremities and carotid arteries in patients with abdominal aorta aneurysm. Artery Res 2016. [DOI: 10.1016/j.artres.2016.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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47
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Lu H, Howatt DA, Balakrishnan A, Moorleghen JJ, Rateri DL, Cassis LA, Daugherty A. Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice. J Vis Exp 2015. [PMID: 26436287 PMCID: PMC4692630 DOI: 10.3791/53191] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5-10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms.
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Affiliation(s)
| | | | | | | | - Debra L Rateri
- Saha Cardiovascular Research Center, University of Kentucky
| | - Lisa A Cassis
- Department of Pharmacology and Nutritional Sciences, University of Kentucky
| | - Alan Daugherty
- Saha Cardiovascular Research Center, University of Kentucky;
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Sun H, Mi X, Gao N, Yan C, Yu FS. Hyperglycemia-suppressed expression of Serpine1 contributes to delayed epithelial wound healing in diabetic mouse corneas. Invest Ophthalmol Vis Sci 2015; 56:3383-92. [PMID: 26024123 DOI: 10.1167/iovs.15-16606] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
PURPOSE Patients with diabetes mellitus (DM) are at an increased risk for developing corneal complications, including delayed wound healing. The purpose of this study was to characterize the expression and the function of Serpine1 and other components of urokinase plasminogen activator (uPA)-proteolytic system in delayed epithelial wound healing in diabetic mouse corneas. METHODS Mice of the strain C57BL/6 were induced to develop diabetes by streptozotocin, and wound-healing assays were performed 10 weeks afterward. Gene expression and/or distribution were assessed by real-time PCR, Western blotting, and/or immunohistochemistry. The role of Serpine1 in mediating epithelial wound closure was determined by subconjunctival injections of neutralizing antibodies in either normal or recombinant protein in diabetic corneas. Enzyme assay for matrix metalloproteinase (MMP)-3 was also performed. RESULTS The expressions of Serpine1 (PAI-1), Plau (uPA), and Plaur (uPA receptor) were upregulated in response to wounding, and these upregulations were significantly suppressed by hyperglycemia. In healing epithelia, Plau and Serpine1 were abundantly expressed at the leading edge of the healing epithelia of normal and, to a lesser extent, diabetic corneas. Inhibition of Serpine1 delayed epithelial wound closure in normal corneas, whereas recombinant Serpine1 accelerated it in diabetic corneas. The Plau and MMP-3 mRNA levels and MMP-3 enzymatic activities were correlated to Serpine1 levels and/or the rates of epithelial wound closure. CONCLUSIONS Serpine1 plays a role in mediating epithelial wound healing and its impaired expression may contribute to delayed wound healing in DM corneas. Hence, modulating uPA proteolytic pathway may represent a new approach for treating diabetic keratopathy.
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Owens AP, Edwards TL, Antoniak S, Geddings JE, Jahangir E, Wei WQ, Denny JC, Boulaftali Y, Bergmeier W, Daugherty A, Sampson UK, Mackman N. Platelet Inhibitors Reduce Rupture in a Mouse Model of Established Abdominal Aortic Aneurysm. Arterioscler Thromb Vasc Biol 2015; 35:2032-2041. [PMID: 26139462 PMCID: PMC4552620 DOI: 10.1161/atvbaha.115.305537] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 06/17/2015] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Rupture of abdominal aortic aneurysms causes a high morbidity and mortality in the elderly population. Platelet-rich thrombi form on the surface of aneurysms and may contribute to disease progression. In this study, we used a pharmacological approach to examine a role of platelets in established aneurysms induced by angiotensin II infusion into hypercholesterolemic mice. APPROACH AND RESULTS Administration of the platelet inhibitors aspirin or clopidogrel bisulfate to established abdominal aortic aneurysms dramatically reduced rupture. These platelet inhibitors reduced abdominal aortic platelet and macrophage recruitment resulting in decreased active matrix metalloproteinase-2 and matrix metalloproteinase-9. Platelet inhibitors also resulted in reduced plasma concentrations of platelet factor 4, cytokines, and components of the plasminogen activation system in mice. To determine the validity of these findings in human subjects, a cohort of aneurysm patients were retrospectively analyzed using developed and validated algorithms in the electronic medical record database at Vanderbilt University. Similar to mice, administration of aspirin or P2Y12 inhibitors was associated with reduced death among patients with abdominal aortic aneurysm. CONCLUSIONS These results suggest that platelets contribute to abdominal aortic aneurysm progression and rupture.
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Affiliation(s)
- A. Phillip Owens
- Department of Medicine Division of Hematology and Oncology, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA Phone: 919-843-3961
| | - Todd L Edwards
- Department of Medicine, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
- Division of Epidemiology, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
| | - Silvio Antoniak
- Department of Medicine Division of Hematology and Oncology, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA Phone: 919-843-3961
| | - Julia E. Geddings
- Department of Medicine Division of Hematology and Oncology, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA Phone: 919-843-3961
| | - Eiman Jahangir
- Department of Cardiovascular Diseases John Ochsner Heart and Vascular Institute Ochsner Clinical School - The University of Queensland School of Medicine New Orleans, LA 70115 Phone: 504-392-3131
| | - Wei-Qi Wei
- Department of Biomedical Informatics, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
| | - Joshua C. Denny
- Department of Biomedical Informatics, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
| | - Yacine Boulaftali
- Department of Medicine Division of Hematology and Oncology, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA Phone: 919-843-3961
| | - Wolfgang Bergmeier
- Department of Biochemistry and Biophysics, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA Phone: 919-843-3961
| | - Alan Daugherty
- Saha Cardiovascular Research Center University of Kentucky Lexington, KY 40536 Phone: 859-323-3512
| | - Uchechukwu K.A. Sampson
- Department of Medicine, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center Nashville, TN 37203 Phone: 615-322-3652
| | - Nigel Mackman
- Department of Medicine Division of Hematology and Oncology, UNC McAllister Heart Institute University of North Carolina at Chapel Hill Chapel Hill, NC 27599, USA Phone: 919-843-3961
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Liu J, Lu H, Howatt DA, Balakrishnan A, Moorleghen JJ, Sorci-Thomas M, Cassis LA, Daugherty A. Associations of ApoAI and ApoB-containing lipoproteins with AngII-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol 2015; 35:1826-34. [PMID: 26044581 DOI: 10.1161/atvbaha.115.305482] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Accepted: 05/20/2015] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Dyslipidemia is implicated in abdominal aortic aneurysms (AAAs) in humans and angiotensin (Ang) II-infused mice. This study determined effects of major lipoprotein classes on AngII-induced AAAs using multiple mouse strains with dietary and pharmacological manipulations. APPROACH AND RESULTS Western diet had minor effects on plasma cholesterol concentrations and the low incidence of AngII-induced AAAs in C57BL/6J mice. Low incidence of AAAs in this strain was not attributed to protection from high-density lipoprotein, because apolipoprotein (apo) AI deficiency did not increase AngII-induced AAAs. ApoAI deletion also failed to alter AAA occurrence in hypercholesterolemic mice. Low-density lipoprotein receptor-/- mice fed normal diet had low incidence of AngII-induced AAAs. Western diet feeding of this strain provoked pronounced hypercholesterolemia because of increased apoB-containing lipoproteins with attendant increases of atherosclerosis in both sexes, but AAAs only in male mice. ApoE-deficient mice fed normal diet were modestly hypercholesterolemic, whereas this strain fed Western diet was severely hypercholesterolemic because of increased apoB-containing lipoprotein concentrations. The latter augmented atherosclerosis, but did not change the high incidence of AAAs in this strain. To determine whether reductions in apoB-containing lipoproteins influenced AngII-induced AAAs, ezetimibe was administered at a dose that partially reduced plasma cholesterol concentrations to ApoE-deficient mice fed Western diet. This decreased atherosclerosis, but not AAAs. This ezetimibe dose in ApoE-deficient mice fed normal diet significantly decreased plasma apoB-containing lipoprotein concentrations and reduced AngII-induced AAAs. CONCLUSIONS ApoB-containing lipoproteins contribute to augmentation of AngII-induced AAA in male mice. However, unlike atherosclerosis, AAA occurrence was not correlated with increases in plasma apoB-containing lipoprotein concentrations.
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Affiliation(s)
- Jing Liu
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Hong Lu
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Deborah A Howatt
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Anju Balakrishnan
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Jessica J Moorleghen
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Mary Sorci-Thomas
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Lisa A Cassis
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.)
| | - Alan Daugherty
- From the Saha Cardiovascular Research Center (J.L., H.L., D.A.H., A.B., J.J.M., A.D.) and Department of Pharmacology and Nutritional Sciences (J.L., L.A.C., A.D.), University of Kentucky, Lexington; and Department of Medicine, Medical College of Wisconsin, Milwaukee (M.S.-T.).
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