|
1
|
Norton CE, Shaw RL, Segal SS. Differential Effects of High Fat Diets on Resilience to H 2O 2-Induced Cell Death in Mouse Cerebral Arteries: Role for Processed Carbohydrates. Antioxidants (Basel) 2023; 12:1433. [PMID: 37507971 PMCID: PMC10376469 DOI: 10.3390/antiox12071433] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/30/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
High fat, western-style diets increase vascular oxidative stress. We hypothesized that smooth muscle cells and endothelial cells adapt during the consumption of high fat diets to become more resilient to acute oxidative stress. Male C57Bl/6J mice were fed a western-style diet high in fat and processed carbohydrates (WD), a high fat diet that induces obesity (DIO), or their respective control (CD) and standard (SD) diets for 16 weeks. Posterior cerebral arteries (PCAs) were isolated and pressurized for study. During acute exposure to H2O2 (200 µM), smooth muscle cell and endothelial cell death were reduced in PCAs from WD, but not DIO mice. WD selectively attenuated mitochondrial membrane potential depolarization and vessel wall Ca2+ influx during H2O2 exposure. Selective inhibition of transient receptor potential (TRP) V4 or TRPC3 channels reduced smooth muscle cell and endothelial cell death in concert with the vessel wall [Ca2+]i response to H2O2 for PCAs from CD mice and eliminated differences between CD and WD. Inhibiting Src kinases reduced smooth muscle cell death along with [Ca2+]i response to H2O2 only in PCAs from CD mice and eliminated differences between diets. However, Src kinase inhibition did not alter endothelial cell death. These findings indicate that consuming a WD, but not high fat alone, leads to adaptations that limit Ca2+ influx and vascular cell death during exposure to acute oxidative stress.
Collapse
Affiliation(s)
- Charles E Norton
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
| | - Rebecca L Shaw
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
| | - Steven S Segal
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Dalton Cardiovascular Research Center, Columbia, MO 65211, USA
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 65201, USA
- Department of Biomedical, Biological and Chemical Engineering, University of Missouri, Columbia, MO 65211, USA
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA
| |
Collapse
|
|
2
|
Xie H, Qin Z, Ling Z, Ge X, Zhang H, Guo S, Liu L, Zheng K, Jiang H, Xu R. Oral pathogen aggravates atherosclerosis by inducing smooth muscle cell apoptosis and repressing macrophage efferocytosis. Int J Oral Sci 2023; 15:26. [PMID: 37380627 DOI: 10.1038/s41368-023-00232-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 05/30/2023] [Accepted: 06/05/2023] [Indexed: 06/30/2023] Open
Abstract
Periodontitis imparting the increased risk of atherosclerotic cardiovascular diseases is partially due to the immune subversion of the oral pathogen, particularly the Porphyromonas gingivalis (P. gingivalis), by inducing apoptosis. However, it remains obscure whether accumulated apoptotic cells in P. gingivalis-accelerated plaque formation are associated with impaired macrophage clearance. Here, we show that smooth muscle cells (SMCs) have a greater susceptibility to P. gingivalis-induced apoptosis than endothelial cells through TLR2 pathway activation. Meanwhile, large amounts of miR-143/145 in P.gingivalis-infected SMCs are extracellularly released and captured by macrophages. Then, these miR-143/145 are translocated into the nucleus to promote Siglec-G transcription, which represses macrophage efferocytosis. By constructing three genetic mouse models, we further confirm the in vivo roles of TLR2 and miR-143/145 in P. gingivalis-accelerated atherosclerosis. Therapeutically, we develop P.gingivalis-pretreated macrophage membranes to coat metronidazole and anti-Siglec-G antibodies for treating atherosclerosis and periodontitis simultaneously. Our findings extend the knowledge of the mechanism and therapeutic strategy in oral pathogen-associated systemic diseases.
Collapse
Affiliation(s)
- Hanyu Xie
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Ziyue Qin
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
- Department of Periodontology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Ziji Ling
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Xiao Ge
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Hang Zhang
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Shuyu Guo
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Laikui Liu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Kai Zheng
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.
| | - Rongyao Xu
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
|
3
|
Guo Z, Wan X, Luo Y, Liang F, Jiang S, Yuan X, Mo Z. The vicious circle of UHRF1 down-regulation and KEAP1/NRF2/HO-1 pathway impairment promotes oxidative stress-induced endothelial cell apoptosis in diabetes. Diabet Med 2023; 40:e15026. [PMID: 36510823 DOI: 10.1111/dme.15026] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/05/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced endothelial cell (EC) apoptosis in diabetes. METHODS Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. RESULTS UHRF1 expression levels were significantly decreased in endothelial colony-forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. CONCLUSION Diabetes-induced oxidative stress can mediate down-regulation of UHRF1, which enhances ROS production by regulating KEAP1/p-NRF2 pathway through histone acetylation and might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further promote oxidative stress-induced apoptosis of ECs in diabetes.
Collapse
Affiliation(s)
- Zi Guo
- Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot Research Centre of Central South University, Changsha, China
| | - Xinxing Wan
- Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot Research Centre of Central South University, Changsha, China
| | - Yufang Luo
- Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot Research Centre of Central South University, Changsha, China
| | - Fang Liang
- Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot Research Centre of Central South University, Changsha, China
| | - Siwei Jiang
- Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot Research Centre of Central South University, Changsha, China
| | - Xiuhong Yuan
- Department of Clinical Psychology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhaohui Mo
- Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot Research Centre of Central South University, Changsha, China
| |
Collapse
|
|
4
|
Tauchi M, Oshita K, Urschel K, Furtmair R, Kühn C, Stumpfe FM, Botos B, Achenbach S, Dietel B. The Involvement of Cx43 in JNK1/2-Mediated Endothelial Mechanotransduction and Human Plaque Progression. Int J Mol Sci 2023; 24:ijms24021174. [PMID: 36674690 PMCID: PMC9863493 DOI: 10.3390/ijms24021174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/23/2022] [Accepted: 12/31/2022] [Indexed: 01/11/2023] Open
Abstract
Atherosclerotic lesions preferentially develop at bifurcations, characterized by non-uniform shear stress (SS). The aim of this study was to investigate SS-induced endothelial activation, focusing on stress-regulated mitogen-activated protein kinases (MAPK) and downstream signaling, and its relation to gap junction proteins, Connexins (Cxs). Human umbilical vein endothelial cells were exposed to flow ("mechanical stimulation") and stimulated with TNF-α ("inflammatory stimulation"). Phosphorylated levels of MAPKs (c-Jun N-terminal kinase (JNK1/2), extracellular signal-regulated kinase (ERK), and p38 kinase (p38K)) were quantified by flow cytometry, showing the activation of JNK1/2 and ERK. THP-1 cell adhesion under non-uniform SS was suppressed by the inhibition of JNK1/2, not of ERK. Immunofluorescence staining and quantitative real-time PCR demonstrated an induction of c-Jun and c-Fos and of Cx43 in endothelial cells by non-uniform SS, and the latter was abolished by JNK1/2 inhibition. Furthermore, plaque inflammation was analyzed in human carotid plaques (n = 40) using immunohistochemistry and quanti-gene RNA-assays, revealing elevated Cx43+ cell counts in vulnerable compared to stable plaques. Cx43+ cell burden in the plaque shoulder correlated with intraplaque neovascularization and lipid core size, while an inverse correlation was observed with fibrous cap thickness. Our results constitute the first report that JNK1/2 mediates Cx43 mechanoinduction in endothelial cells by atheroprone shear stress and that Cx43 is expressed in human carotid plaques. The correlation of Cx43+ cell counts with markers of plaque vulnerability implies its contribution to plaque progression.
Collapse
Affiliation(s)
- Miyuki Tauchi
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Cognitive and Molecular Research Institute of Brain Diseases, Kurume University, Kurume 830-0011, Japan
| | - Kensuke Oshita
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Department of Anesthesiology, School of Medicine, Kurume University, Kurume 830-0011, Japan
| | - Katharina Urschel
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Roman Furtmair
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Constanze Kühn
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Florian M. Stumpfe
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Balazs Botos
- Department of Vascular Surgery, Hospital of Nürnberg-Süd, 90471 Nürnberg, Germany
| | - Stephan Achenbach
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Barbara Dietel
- Department of Cardiology and Angiology, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Correspondence:
| |
Collapse
|
|
5
|
Mason SA, Parker L, van der Pligt P, Wadley GD. Vitamin C supplementation for diabetes management: A comprehensive narrative review. Free Radic Biol Med 2023; 194:255-283. [PMID: 36526243 DOI: 10.1016/j.freeradbiomed.2022.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
Growing evidence suggests that vitamin C supplementation may be an effective adjunct therapy in the management of people with diabetes. This paper critically reviews the current evidence on effects of vitamin C supplementation and its potential mechanisms in diabetes management. Evidence from meta-analyses of randomized controlled trials (RCTs) show favourable effects of vitamin C on glycaemic control and blood pressure that may be clinically meaningful, and mixed effects on blood lipids and endothelial function. However, evidence is mostly of low evidence certainty. Emerging evidence is promising for effects of vitamin C supplementation on some diabetes complications, particularly diabetic foot ulcers. However, there is a notable lack of robust and well-designed studies exploring effects of vitamin C as a single compound supplement on diabetes prevention and patient-important outcomes (i.e. prevention and amelioration of diabetes complications). RCTs are also required to investigate potential preventative or ameliorative effects of vitamin C on gestational diabetes outcomes. Oral vitamin C doses of 500-1000 mg per day are potentially effective, safe, and affordable for many individuals with diabetes. However, personalisation of supplementation regimens that consider factors such as vitamin C status, disease status, current glycaemic control, vitamin C intake, redox status, and genotype is important to optimize vitamin C's therapeutic effects safely. Finally, given a high prevalence of vitamin C deficiency in patients with complications, it is recommended that plasma vitamin C concentration be measured and monitored in the clinic setting.
Collapse
Affiliation(s)
- Shaun A Mason
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.
| | - Lewan Parker
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Paige van der Pligt
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia; Department of Nutrition and Dietetics, Western Health, Footscray, Australia
| | - Glenn D Wadley
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| |
Collapse
|
|
6
|
Yin Q, Zang G, Li N, Sun C, Du R. Agonist-induced Piezo1 activation promote mitochondrial-dependent apoptosis in vascular smooth muscle cells. BMC Cardiovasc Disord 2022; 22:287. [PMID: 35751027 PMCID: PMC9233385 DOI: 10.1186/s12872-022-02726-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 06/15/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Mechanical damage plays an essential role in the progression of atherosclerosis. Piezo1 is a new mechanically sensitive ion channel. The present study investigated the vascular smooth muscle cells (VSMCs) apoptosis induced by Piezo1 activation and explored its underlying mechanism. METHODS We evaluated cell viability and apoptosis rate with cell counting kit-8 (CCK-8) and Annexin V-FITC/PI flow cytometry assay, respectively. And then Western blot was performed to measure the relative protein. Reactive oxygen species (ROS) and intracellular Ca2+ were assessed via fluorescence microscope, and the mitochondrial transmembrane potential was monitored by JC-10 staining. RESULTS Our in vitro study revealed that mice in the ApoE-/- group compared with control mice showed higher Piezo1 expression(P < 0.05). Besides, Yoda1, a Piezo1 agonist, triggered Ca2+ overload, mitochondrial damage, accumulation of ROS, and VSMCs apoptosis in a dose-depend manner. Furthermore, BAPT-AM (an intracellular Ca2+ chelator) and NAC (an antioxidant) suppressed the mitochondrial damage and attenuated the VSMCs apoptosis. CONCLUSION Our study suggested that Piezo1 induced VSMCs apoptosis because of Ca2+ overload, excessive ROS generation, and mitochondrial dysfunction, which indicated that Piezo1 has potential value in treating vascular diseases.
Collapse
Affiliation(s)
- Qing Yin
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China.,School of Medicine, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Guangyao Zang
- School of Medicine, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Nannan Li
- School of Medicine, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Chenchen Sun
- School of Medicine, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Rongzeng Du
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China.
| |
Collapse
|
|
7
|
Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27072048. [PMID: 35408447 PMCID: PMC9000463 DOI: 10.3390/molecules27072048] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 01/08/2023]
Abstract
The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
Collapse
|
|
8
|
HDL and Endothelial Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1377:27-47. [DOI: 10.1007/978-981-19-1592-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
9
|
Jaworska K, Koper M, Ufnal M. Gut microbiota and renin-angiotensin system: a complex interplay at local and systemic levels. Am J Physiol Gastrointest Liver Physiol 2021; 321:G355-G366. [PMID: 34405730 PMCID: PMC8486428 DOI: 10.1152/ajpgi.00099.2021] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gut microbiota is a potent biological modulator of many physiological and pathological states. The renin-angiotensin system (RAS), including the local gastrointestinal RAS (GI RAS), emerges as a potential mediator of microbiota-related effects. The RAS is involved in cardiovascular system homeostasis, water-electrolyte balance, intestinal absorption, glycemic control, inflammation, carcinogenesis, and aging-related processes. Ample evidence suggests a bidirectional interaction between the microbiome and RAS. On the one hand, gut bacteria and their metabolites may modulate GI and systemic RAS. On the other hand, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition. Notably, the pharmacodynamic effects of the RAS-targeted therapies may be in part mediated by the intestinal RAS and changes in the microbiome. This review summarizes studies on gut microbiota and RAS physiology. Expanding the research on this topic may lay the foundation for new therapeutic paradigms in gastrointestinal diseases and multiple systemic disorders.
Collapse
Affiliation(s)
- Kinga Jaworska
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Koper
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| |
Collapse
|
|
10
|
Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy. Cells 2020; 9:cells9071703. [PMID: 32708634 PMCID: PMC7407143 DOI: 10.3390/cells9071703] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 12/17/2022] Open
Abstract
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been reported to mediate antioxidant, anti-inflammatory, and anti-angiogenic effects in endothelial cells. This study investigated the influence of CBD on the expression of heme oxygenase-1 (HO-1) and its functional role in regulating metabolic, autophagic, and apoptotic processes of human umbilical vein endothelial cells (HUVEC). Concentrations up to 10 µM CBD showed a concentration-dependent increase of HO-1 mRNA and protein and an increase of the HO-1-regulating transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). CBD-induced HO-1 expression was not decreased by antagonists of cannabinoid-activated receptors (CB1, CB2, transient receptor potential vanilloid 1), but by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC). The incubation of HUVEC with 6 µM CBD resulted in increased metabolic activity, while 10 µM CBD caused decreased metabolic activity and an induction of apoptosis, as demonstrated by enhanced caspase-3 cleavage. In addition, CBD triggered a concentration-dependent increase of the autophagy marker LC3A/B-II. Both CBD-induced LC3A/B-II levels and caspase-3 cleavage were reduced by NAC. The inhibition of autophagy by bafilomycin A1 led to apoptosis induction by 6 µM CBD and a further increase of the proapoptotic effect of 10 µM CBD. On the other hand, the inhibition of HO-1 activity with tin protoporphyrin IX (SnPPIX) or knockdown of HO-1 expression by Nrf2 siRNA was associated with a decrease in CBD-mediated autophagy and apoptosis. In summary, our data show for the first time ROS-mediated HO-1 expression in endothelial cells as a mechanism by which CBD mediates protective autophagy, which at higher CBD concentrations, however, can no longer prevent cell death inducing apoptosis.
Collapse
|
|
11
|
Norton CE, Jacobsen NL, Sinkler SY, Manrique-Acevedo C, Segal SS. Female sex and Western-style diet protect mouse resistance arteries during acute oxidative stress. Am J Physiol Cell Physiol 2019; 318:C627-C639. [PMID: 31891519 DOI: 10.1152/ajpcell.00342.2019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
A Western-style diet (WD; high in fat and carbohydrates) increases vascular oxidative stress. We hypothesized that vascular cells adapt to a WD by developing resilience to oxidative stress. Male and female C57BL/6J mice (4 wk of age) were fed a control diet (CD) or a WD for 16-20 wk. Superior epigastric arteries (SEAs; diameter, ~125 µm) were isolated and pressurized for study. Basal reactive oxygen species production was greatest in SEAs from males fed the WD. During exposure to H2O2 (200 μM, 50 min), propidium iodide staining identified nuclei of disrupted endothelial cells (ECs) and smooth muscle cells (SMCs). For mice fed the CD, death of SMCs (21%) and ECs (6%) was greater (P < 0.05) in SEAs from males than females (9% and 2%, respectively). WD consumption attenuated cell death most effectively in SEAs from males. With no difference at rest, H2O2 increased intracellular Ca2+ concentration ([Ca2+]i) to the greatest extent in SEAs from males, as shown by fura 2 fluorescence. Selective disruption of the endothelium (luminal air bubble) increased [Ca2+]i and SMC death during H2O2 exposure irrespective of sex; the WD reduced both responses most effectively in males. Nonselective transient receptor potential (TRP) channel inhibition (ruthenium red, 5 μM) attenuated the rise of [Ca2+]i, as did selective inhibition of TRP vanilloid type 4 (TRPV4) channels (HC-067047, 1 μM), which also attenuated cell death. In contrast, inhibition of voltage-gated Ca2+ channels (diltiazem, 50 μM) was without effect. Thus, for resistance arteries during acute oxidative stress: 1) ECs are more resilient than (and can protect) SMCs, 2) vessels from females are inherently more resilient than those from males, and 3) a WD increases vascular resilience by diminishing TRPV4 channel-dependent Ca2+ entry.
Collapse
Affiliation(s)
- Charles E Norton
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Nicole L Jacobsen
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Shenghua Y Sinkler
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Camila Manrique-Acevedo
- Department of Medicine, University of Missouri, Columbia, Missouri.,Research Services, Harry S Truman Memorial Veterans Hospital, Columbia, Missouri.,Dalton Cardiovascular Research Center, Columbia, Missouri
| | - Steven S Segal
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri.,Dalton Cardiovascular Research Center, Columbia, Missouri
| |
Collapse
|
|
12
|
Mahdavi Gorabi A, Banach M, Reiner Ž, Pirro M, Hajighasemi S, Johnston TP, Sahebkar A. The Role of Mesenchymal Stem Cells in Atherosclerosis: Prospects for Therapy via the Modulation of Inflammatory Milieu. J Clin Med 2019; 8:E1413. [PMID: 31500373 PMCID: PMC6780166 DOI: 10.3390/jcm8091413] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a chronic, inflammatory disease that mainly affects the arterial intima. The disease is more prevalent in middle-age and older individuals with one or more cardiovascular risk factors, including dyslipidemia, hypertension, diabetes, smoking, obesity, and others. The beginning and development of atherosclerosis has been associated with several immune components, including infiltration of inflammatory cells, monocyte/macrophage-derived foam cells, and inflammatory cytokines and chemokines. Mesenchymal stem cells (MSCs) originate from several tissue sources of the body and have self-renewal and multipotent differentiation characteristics. They also have immunomodulatory and anti-inflammatory properties. Recently, it was shown that MSCs have a regulatory role in plasma lipid levels. In addition, MSCs have shown to have promising potential in terms of treatment strategies for several diseases, including those with an inflammatory component. In this regard, transplantation of MSCs to patients with atherosclerosis has been proposed as a novel strategy in the treatment of this disease. In this review, we summarize the current advancements regarding MSCs for the treatment of atherosclerosis.
Collapse
Affiliation(s)
- Armita Mahdavi Gorabi
- Department of Basic and Clinical Research, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), 93-338 Lodz, Poland
| | - Željko Reiner
- Department of Internal medicine, University Hospital Center Zagreb, Kišpatićeva 12, Zagreb 1000, Croatia
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, 06123 Perugia, Italy
| | - Saeideh Hajighasemi
- Department of Medical Biotechnology, Faculty of Paramedicine, Qazvin University of Medical Sciences, Qazvin 1531534199, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64110, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
| |
Collapse
|
|
13
|
ACE inhibitor suppresses cardiac remodeling after myocardial infarction by regulating dendritic cells and AT 2 receptor-mediated mechanism in mice. Biomed Pharmacother 2019; 114:108660. [PMID: 30974387 DOI: 10.1016/j.biopha.2019.108660] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 01/10/2023] Open
Abstract
Dendritic cells (DCs) play a complex role in the progression of myocardial infarction (MI). The impact of angiotensin-converting enzyme (ACE) inhibitor therapy, partly via affecting DCs maturation and recruitment, was tested on a MI mouse model. Furthermore, the cardioprotective effects of ACEI were enhanced through attenuating migration of DCs from the spleen into peripheral circulation, thereby inhibiting DCs maturation and tissue inflammation. ACEI repress DCs immune inflammatory response through down-regulating DCs maturation surface markers and regulating inflammatory cytokines, which led to a higher survival rate, improved function and remodeling through decreased inflammatory response after MI. However, inhibition of AT2R activation, resulted in a reduction of ACEI effects on DCs. The potent anti-inflammatory effect of ACEI can partially be attributed to its impact on DCs through activation of AT2R, which may provide a new target mechanism for ACEI therapy after MI.
Collapse
|
|
14
|
Schwartz M, Böckmann S, Borchert P, Hinz B. SB202190 inhibits endothelial cell apoptosis via induction of autophagy and heme oxygenase-1. Oncotarget 2018; 9:23149-23163. [PMID: 29796178 PMCID: PMC5955409 DOI: 10.18632/oncotarget.25234] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 03/29/2018] [Indexed: 12/20/2022] Open
Abstract
Activation of the p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in various detrimental events finally leading to endothelial dysfunction. The present study therefore investigates the impact of the p38 MAPK inhibitor SB202190 on the expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) as well as metabolic activity, apoptosis and autophagy of endothelial cells. Using human umbilical vein endothelial cells (HUVEC) SB202190 was found to cause a time- and concentration-dependent induction of HO-1 protein. Induction of HO-1 protein expression was mimicked by SB203580, another p38 MAPK inhibitor, but not by SB202474, an inactive structural analogue of p38 MAPK inhibitors. HO-1 induction by both SB202190 and SB203580 was also demonstrated by analysis of mRNA expression. On the functional level, SB202190 was shown to increase metabolic activity and autophagy of HUVEC along with diminishing basal apoptosis. Treatment of cells with tin protoporphyrin IX (SnPPIX), a well-characterised HO-1 enzymatic inhibitor, or HO-1 siRNA left SB202190-modulated metabolic activity and autophagy virtually unaltered but caused a significant reversal of the anti-apoptotic action of SB202190. Conversely, however, HO-1 expression by SB202190 became completely suppressed by the autophagy inhibitor bafilomycin A1. Bafilomycin A1 likewise fully reversed effects of SB202190 on metabolic activity and apoptosis, albeit significantly inducing apoptosis per se. Collectively, this work demonstrates SB202190 to confer upstream induction of autophagy followed by HO-1 induction resulting in potential protective effects against apoptosis. On the other hand, our data oppose HO-1 to contribute to SB202190-mediated increases in metabolic activity and autophagy, respectively.
Collapse
Affiliation(s)
- Margit Schwartz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - Sabine Böckmann
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - Philipp Borchert
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| |
Collapse
|
|
15
|
Leszczynska A, Murphy JM. Vascular Calcification: Is it rather a Stem/Progenitor Cells Driven Phenomenon? Front Bioeng Biotechnol 2018; 6:10. [PMID: 29479528 PMCID: PMC5811524 DOI: 10.3389/fbioe.2018.00010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/22/2018] [Indexed: 12/21/2022] Open
Abstract
Vascular calcification (VC) has witnessed a surge of interest. Vasculature is virtually an omnipresent organ and has a notably high capacity for repair throughout embryonic and adult life. Of the vascular diseases, atherosclerosis is a leading cause of morbidity and mortality on account of ectopic cartilage and bone formation. Despite the identification of a number of risk factors, all the current theories explaining pathogenesis of VC in atherosclerosis are far from complete. The most widely accepted response to injury theory and smooth muscle transdifferentiation to explain the VC observed in atherosclerosis is being challenged. Recent focus on circulating and resident progenitor cells in the vasculature and their role in atherogenesis and VC has been the driving force behind this review. This review discusses intrinsic cellular players contributing to fate determination of cells and tissues to form ectopic cartilage and bone formation.
Collapse
Affiliation(s)
- Aleksandra Leszczynska
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - J Mary Murphy
- Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland
| |
Collapse
|
|
16
|
Li F, Guo X, Chen SY. Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis. Front Cardiovasc Med 2017; 4:32. [PMID: 28589127 PMCID: PMC5438961 DOI: 10.3389/fcvm.2017.00032] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/01/2017] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.
Collapse
Affiliation(s)
- Feifei Li
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA.,The Department of Cardiovascular Surgery, Union Hospital, Wuhan, China
| | - Xia Guo
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA
| | - Shi-You Chen
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA
| |
Collapse
|
|
17
|
Han H, Chen Y, Zhu Z, Su X, Ni J, Du R, Zhang R, Jin W. p-Cresyl sulfate promotes the formation of atherosclerotic lesions and induces plaque instability by targeting vascular smooth muscle cells. Front Med 2016; 10:320-9. [PMID: 27527366 DOI: 10.1007/s11684-016-0463-x] [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: 03/31/2016] [Accepted: 06/12/2016] [Indexed: 12/17/2022]
Abstract
Coronary atherosclerosis is a major complication of chronic kidney disease. This condition contributes to the increased mortality in dialysis patients. p-Cresyl sulfate (PCS) is a prototype of protein-bound uremic toxins that cannot be efficiently removed through routine dialysis procedures. In the present study, ApoE(-/-) mice that underwent 5/6 nephrectomy were randomly divided into two groups, namely, vehicle-treated group (n = 20) and PCS-treated group (n = 20). Mice were sacrificed for en face and immunohistological analyses after 8 or 24 weeks of high-fat diet. Rat aortic vascular smooth muscle cells (VSMCs) were treated with phosphate buffer solution or 500 μmol/L PCS for in vitro evaluation. PCS-treated mice were observed to suffer increased atherosclerotic lesions after eight weeks of PCS administration. Moreover, 24 weeks of PCS administration also markedly increased the vulnerability index of aortic plaques. PCS was also observed to facilitate the migration and proliferation of VSMCs during the progression of the disease. Moreover, PCS disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques. Thus, PCS played a vital role in promoting atherogenesis and disturbing the stability of formed plaques probably by targeting VSMCs.
Collapse
Affiliation(s)
- Hui Han
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yanjia Chen
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhengbin Zhu
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiuxiu Su
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jingwei Ni
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Run Du
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ruiyan Zhang
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. .,Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Wei Jin
- Department of Cardiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| |
Collapse
|
|
18
|
Imaizumi S, Miura SI, Takata K, Takamiya Y, Kuwano T, Sugihara M, Ike A, Iwata A, Nishikawa H, Saku K. Association between cholesterol efflux capacity and coronary restenosis after successful stent implantation. Heart Vessels 2015; 31:1257-65. [DOI: 10.1007/s00380-015-0738-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 08/28/2015] [Indexed: 10/23/2022]
|
|
19
|
Wang SS, Hu SW, Zhang QH, Xia AX, Jiang ZX, Chen XM. Mesenchymal Stem Cells Stabilize Atherosclerotic Vulnerable Plaque by Anti-Inflammatory Properties. PLoS One 2015; 10:e0136026. [PMID: 26288013 PMCID: PMC4546153 DOI: 10.1371/journal.pone.0136026] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 07/30/2015] [Indexed: 01/22/2023] Open
Abstract
Background and objectives Formation and progression of atherosclerotic vulnerable plaque (VP) is the primary cause of many cardio-cerebrovascular diseases such as acute coronary syndrome and stroke. It has been reported that bone marrow mesenchymal stem cells (MSC) exhibit protective effects against many kinds of diseases including myocardial infarction. Here, we examined the effects of intravenous MSC infusion on a VP model and provide novel evidence of its influence as a therapy in this animal disease model. Subjects and methods Thirty healthy male New Zealand white rabbits were randomly divided into a MSC, VP or stable plaque (SP) group (n = 10/group) and received high fat diet and cold-induced common carotid artery intimal injury with liquid nitrogen to form atherosclerotic plaques. Serum hs-CRP, TNF-α, IL-6 and IL-10 levels were measured by ELISA at 1, 2, 3, 7, 14, 21 and 28 days after MSC transplantation. The animals were sacrificed at 4 weeks after MSC transplantation. Lesions in the right common carotid were observed using H&E and Masson staining, and the fibrous cap/lipid core ratio of atherosclerotic plaques were calculated. The expression of nuclear factor κB (NF-κB) and matrix metalloproteinase 1, 2, 9 (MMP-1,2,9) in the plaque were detected using immunohistochemistry, and apoptotic cells in the plaques were detected by TUNEL. In addition, the level of TNF-α stimulated gene/protein 6 (TSG-6) mRNA and protein were measured by quantitative Real-Time PCR and Western blotting, respectively. Results Two rabbits in the VP group died of lung infection and cerebral infarction respectively at 1 week after plaque injury by liquid nitrogen. Both H&E and Masson staining revealed that the plaques from the SP and MSC groups had more stable morphological structure and a larger fibrous cap/lipid core ratio than the VP group. Serum hs-CRP, TNF-α and IL-6 were significantly down-regulated, whereas IL-10 was significantly up-regulated in the MSC group compared with the VP group. .Immunohistochemistry analysis revealed that NF-κB and MMP expression was reduced in the MSC and SP groups compared to the VP group. Cell apoptosis decreased significantly in both the MSC and SP groups in comparison to the VP group. TSG-6 mRNA and protein expression were higher in the plaques of the MSC group compared to the VP and SP groups. Conclusions Our study results suggest that MSC transplantation can effectively stabilize vulnerable plaques in atherosclerotic rabbits. This may potentially offer a new clinical application of MSC in atherosclerosis.
Collapse
Affiliation(s)
- Shuang-shuang Wang
- College of Medicine, Zhejiang University, Hangzhou, 310009, China
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Si-wang Hu
- Department of Spine Surgery, Affiliated Hospital of Medical College of Ningbo University, Ningbo 315000, China
| | | | | | - Zhi-xin Jiang
- Chinese PLA 305 hospital, Beijing 100017, China
- * E-mail: (XMC); (ZXJ)
| | - Xiao-min Chen
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
- * E-mail: (XMC); (ZXJ)
| |
Collapse
|
|
20
|
Riwanto M, Rohrer L, von Eckardstein A, Landmesser U. Dysfunctional HDL: from structure-function-relationships to biomarkers. Handb Exp Pharmacol 2015; 224:337-366. [PMID: 25522994 DOI: 10.1007/978-3-319-09665-0_10] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipid-modifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.
Collapse
Affiliation(s)
- Meliana Riwanto
- Cardiology, University Heart Center, University Hospital Zurich and Center of Molecular Cardiology, University of Zurich, Rämistrasse 100, CH 8091, Zurich, Switzerland
| | | | | | | |
Collapse
|
|
21
|
|
|
22
|
Andrikopoulos GK, Alexopoulos DK, Gartaganis SP. Pseudoexfoliation syndrome and cardiovascular diseases. World J Cardiol 2014; 6:847-854. [PMID: 25228963 PMCID: PMC4163713 DOI: 10.4330/wjc.v6.i8.847] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 04/09/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Pseudoexfoliation (PEX) syndrome is a well-recognized late-onset disease caused by a generalized fibrillopathy. It is linked to a broad spectrum of ocular complications including glaucoma and perioperative problems during cataract surgery. Apart from the long-known intraocular manifestations, PEX deposits have been found in a variety of extraocular locations and they appear to represent a systemic process associated with increased cardiovascular and cerebrovascular morbidity. However, as published results are inconsistent, the clinical significance of the extraocular PEX deposits remains controversial. Identification of PEX deposits in the heart and the vessel wall, epidemiologic studies, as well as, similarities in pathogenetic mechanisms have led to the hypothesis of a possible relation between fibrillar material and cardiovascular disease. Recent studies suggest that PEX syndrome is frequently linked to impaired heart and blood vessels function. Systemic and ocular blood flow changes, altered parasympathetic vascular control and baroreflex sensitivity, increased vascular resistance and decreased blood flow velocity, arterial endothelial dysfunction, high levels of plasma homocysteine and arterial hypertension have all been demonstrated in PEX subjects. Common features in the pathogenesis of both atherosclerosis and PEX, like oxidative stress and inflammation and a possible higher frequency of abdominal aorta aneurysm in PEX patients, could imply that these grey-white deposits and cardiovascular disorders are related or reflect different manifestations of the same process.
Collapse
|
|
23
|
Kratzer A, Giral H, Landmesser U. High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease. Cardiovasc Res 2014; 103:350-61. [DOI: 10.1093/cvr/cvu139] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
|
|
24
|
Afridi HI, Kazi TG, Talpur FN, Kazi A, Arain SS, Arain SA, Brahman KD, Panhwar AH. Interaction between selenium and mercury in biological samples of Pakistani myocardial infarction patients at different stages as related to controls. Biol Trace Elem Res 2014; 158:143-51. [PMID: 24643467 DOI: 10.1007/s12011-014-9932-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 03/03/2014] [Indexed: 11/30/2022]
Abstract
It has been speculated that trace elements may a play role in the pathogenesis of heart diseases. In the present study, we aimed to assess the levels of selenium (Se) and mercury (Hg) in biological samples (whole blood, urine, and scalp hair) of myocardial infarction (MI) patients of both genders (age range 45-60 years) at the first, second, and third heart attack (n = 130), hospitalized in a cardiac ward of a civil hospital of Hyderabad City (Pakistan). For comparison, healthy age-matched referent subjects (n = 61) of both genders were also selected. Se and Hg in biological samples were measured by electrothermal atomic absorption spectrometry and cold vapor atomic absorption spectrometry, prior to microwave acid digestion, respectively. The validity of the methodology was checked by biological certified reference materials. During this study, 78 % of the 32 registered patients of third MI attack (aged >50 years) died. The concentration of Se was decreased in scalp hair and blood samples of MI patients, while Hg was higher in all biological samples as compared to referent subjects. Se concentration was inversely associated with the risk of MI attacks in both genders. These results add to an increasing body of evidence that Se is a protective element for cardiovascular health.
Collapse
Affiliation(s)
- Hassan Imran Afridi
- National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan,
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Benhamou Y, Bellien J, Armengol G, Gomez E, Richard V, Lévesque H, Joannidès R. [Assessment of endothelial function in autoimmune diseases]. Rev Med Interne 2014; 35:512-23. [PMID: 24412013 DOI: 10.1016/j.revmed.2013.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 11/07/2013] [Accepted: 12/02/2013] [Indexed: 11/15/2022]
Abstract
Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to an increase in cardiovascular disease incidence. In addition to traditional cardiovascular risk factors, endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory and a proadhesive state, and prothrombic properties. Therefore, assessment of endothelial dysfunction targets this vascular phenotype using several biological markers as indicators of endothelial dysfunction. Measurements of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin), pro-thrombotic factors (thrombomodulin, von Willebrand factor, plasminogen activator inhibitor-1) and inflammatory cytokines are most often performed. Regarding the functional assessment of the endothelium, the flow-mediated dilatation of conduit arteries is a non-invasive method widely used in pathophysiological and interventional studies. In this review, we will briefly review the most relevant information upon endothelial dysfunction mechanisms and explorations. We will summarize the similarities and differences in the biological and functional assessments of the endothelium in different autoimmune diseases.
Collapse
Affiliation(s)
- Y Benhamou
- Département de médecine interne, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France; Service de pharmacologie, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France; Inserm U 1096, faculté de médecine de Rouen, 22, boulevard Gambetta, 76183 Rouen cedex, France.
| | - J Bellien
- Département de médecine interne, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France; Service de pharmacologie, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France
| | - G Armengol
- Département de médecine interne, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France
| | - E Gomez
- Inserm U 1096, faculté de médecine de Rouen, 22, boulevard Gambetta, 76183 Rouen cedex, France
| | - V Richard
- Inserm U 1096, faculté de médecine de Rouen, 22, boulevard Gambetta, 76183 Rouen cedex, France
| | - H Lévesque
- Département de médecine interne, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France; Inserm U 1096, faculté de médecine de Rouen, 22, boulevard Gambetta, 76183 Rouen cedex, France
| | - R Joannidès
- Service de pharmacologie, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France; Inserm U 1096, faculté de médecine de Rouen, 22, boulevard Gambetta, 76183 Rouen cedex, France
| |
Collapse
|
|
26
|
Riwanto M, Landmesser U. High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease. J Lipid Res 2013; 54:3227-43. [PMID: 23873269 DOI: 10.1194/jlr.r037762] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Prospective population studies in the primary prevention setting have shown that reduced plasma levels of HDL cholesterol are associated with an increased risk of coronary disease and myocardial infarction. Experimental and translational studies have further revealed several potential anti-atherogenic effects of HDL, including protective effects on endothelial cell functions. HDL has been suggested to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Moreover, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and anti-inflammatory, anti-apoptotic, and anti-thrombotic effects as well as endothelial repair processes. However, several recent clinical trials using HDL cholesterol-raising agents, such as torcetrapib, dalcetrapib, and niacin, did not demonstrate a significant reduction of cardiovascular events in patients with coronary disease. Of note, growing evidence suggests that the vascular effects of HDL can be highly heterogeneous and vasoprotective properties of HDL are altered in patients with coronary disease. Characterization of underlying mechanisms and understanding of the clinical relevance of this "HDL dysfunction" is currently an active field of cardiovascular research. Notably, in some recent studies no clear association of higher HDL cholesterol levels with a reduced risk of cardiovascular events was observed in patients with already established coronary disease. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies. In this review, we will address different effects of HDL on endothelial cell functions potentially relevant to atherosclerotic vascular disease and explore molecular mechanisms leading to "dysfunctional HDL".
Collapse
Affiliation(s)
- Meliana Riwanto
- Cardiology, University Heart Center, University Hospital Zurich and Cardiovascular Research, Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | | |
Collapse
|
|
27
|
Abstract
In addition to its role in reverse cholesterol transport, high-density lipoprotein (HDL) cholesterol has direct action on numerous cell types that influence cardiovascular and metabolic health. Cellular responses to HDL entail its capacity to invoke cholesterol efflux that causes signal initiation via scavenger receptor class B, type I, and plasma membrane receptor activation by HDL cargo molecules. In endothelial cells and their progenitors, HDL attenuates apoptosis and stimulates proliferation and migration. HDL also has diverse anti-inflammatory actions in both endothelial cells and leukocytes. In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. There are additional actions of HDL of potential cardiovascular consequence that are indirect, including the capacities to promote pancreatic β-cell insulin secretion, to protect pancreatic β cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties. Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health.
Collapse
Affiliation(s)
- Chieko Mineo
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | |
Collapse
|
|
28
|
Abstract
In addition to its role in reverse cholesterol transport, high-density lipoprotein (HDL) cholesterol has direct action on numerous cell types that influence cardiovascular and metabolic health. Cellular responses to HDL entail its capacity to invoke cholesterol efflux that causes signal initiation via scavenger receptor class B, type I, and plasma membrane receptor activation by HDL cargo molecules. In endothelial cells and their progenitors, HDL attenuates apoptosis and stimulates proliferation and migration. HDL also has diverse anti-inflammatory actions in both endothelial cells and leukocytes. In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. There are additional actions of HDL of potential cardiovascular consequence that are indirect, including the capacities to promote pancreatic β-cell insulin secretion, to protect pancreatic β cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties. Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health.
Collapse
Affiliation(s)
- Chieko Mineo
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | |
Collapse
|
|
29
|
Baumgartner-Parzer SM, Waldenberger FR, Freudenthaler A, Ginouvès-Guerdoux A, McGahie D, Gatto H. The natural antioxidants, pomegranate extract and soy isoflavones, favourably modulate canine endothelial cell function. ISRN VETERINARY SCIENCE 2012; 2012:590328. [PMID: 23762588 PMCID: PMC3671723 DOI: 10.5402/2012/590328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 10/26/2012] [Indexed: 11/23/2022]
Abstract
Cardiovascular disease, preceded by vascular endothelial dysfunction, is a prominent cause of death in dogs. L-carnitine and taurine, well known for their antioxidative capacity, beneficially affect cardiovascular disease as well as certain dog cardiomyopathies. It is well established that vascular endothelial dysfunction precedes cardiovascular disease and that “vasoprotective factors” (NO and antioxidants) prevent apoptosis, whereas “risk factors” such as oxidized LDL, hyperglycemia, and free fatty acids trigger it in cultured human vascular endothelial cells. Whereas human vascular cell in vitro models are widely established and used for the characterisation of potential vasoprotective substances, such models are not available for canine endothelial cells. In the present study we therefore developed an in vitro model, which allows the testing of the effects of different substances on proliferation and apoptosis in canine aortic endothelial cells. This model was used to test L-carnitine, taurine, pomegranate extract, and Soy Isoflavones in comparison to reference substances (glutathione and pioglitazone) previously shown to modulate human endothelial cell function. L-carnitine and taurine neither exhibited antiproliferative nor antiapoptotic activities in the context of this study. However extracts from pomegranate and soy isoflavones dramatically reduced proliferation and apoptosis in a dose dependent fashion, being in line with a vasoprotective activity in dogs.
Collapse
Affiliation(s)
- Sabina M Baumgartner-Parzer
- Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | | | | | | | | | | |
Collapse
|
|
30
|
Viswanathan K, Bot I, Liu L, Dai E, Turner PC, Togonu-Bickersteth B, Richardson J, Davids JA, Williams JM, Bartee MY, Chen H, van Berkel TJC, Biessen EAL, Moyer RW, Lucas AR. Viral cross-class serpin inhibits vascular inflammation and T lymphocyte fratricide; a study in rodent models in vivo and human cell lines in vitro. PLoS One 2012; 7:e44694. [PMID: 23049756 PMCID: PMC3458838 DOI: 10.1371/journal.pone.0044694] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 08/10/2012] [Indexed: 12/25/2022] Open
Abstract
Poxviruses express highly active inhibitors, including serine proteinase inhibitors (serpins), designed to target host immune defense pathways. Recent work has demonstrated clinical efficacy for a secreted, myxomaviral serpin, Serp-1, which targets the thrombotic and thrombolytic proteases, suggesting that other viral serpins may have therapeutic application. Serp-2 and CrmA are intracellular cross-class poxviral serpins, with entirely distinct functions from the Serp-1 protein. Serp-2 and CrmA block the serine protease granzyme B (GzmB) and cysteine proteases, caspases 1 and 8, in apoptotic pathways, but have not been examined for extracellular anti-inflammatory activity. We examined the ability of these cross-class serpins to inhibit plaque growth after arterial damage or transplant and to reduce leukocyte apoptosis. We observed that purified Serp-2, but not CrmA, given as a systemic infusion after angioplasty, transplant, or cuff-compression injury markedly reduced plaque growth in mouse and rat models in vivo. Plaque growth was inhibited both locally at sites of surgical trauma, angioplasty or transplant, and systemically at non-injured sites in ApoE-deficient hyperlipidemic mice. With analysis in vitro of human cells in culture, Serp-2 selectively inhibited T cell caspase activity and blocked cytotoxic T cell (CTL) mediated killing of T lymphocytes (termed fratricide). Conversely, both Serp-2 and CrmA inhibited monocyte apoptosis. Serp-2 inhibitory activity was significantly compromised either in vitro with GzmB antibody or in vivo in ApoE/GzmB double knockout mice. Conclusions The viral cross-class serpin, Serp-2, that targets both apoptotic and inflammatory pathways, reduces vascular inflammation in a GzmB-dependent fashion in vivo, and inhibits human T cell apoptosis in vitro. These findings indicate that therapies targeting Granzyme B and/or T cell apoptosis may be used to inhibit T lymphocyte apoptosis and inflammation in response to arterial injury.
Collapse
Affiliation(s)
| | - Ilze Bot
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
- University of Maastracht, Maastracht, The Netherlands
| | - Liying Liu
- Vascular Biology Research Group, Robarts' Research Institute, London, Canada
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
| | - Erbin Dai
- Vascular Biology Research Group, Robarts' Research Institute, London, Canada
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
| | - Peter C. Turner
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Babajide Togonu-Bickersteth
- Vascular Biology Research Group, Robarts' Research Institute, London, Canada
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
| | - Jakob Richardson
- Vascular Biology Research Group, Robarts' Research Institute, London, Canada
| | - Jennifer A. Davids
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Jennifer M. Williams
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
| | - Mee Y. Bartee
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Hao Chen
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
| | - Theo J. C. van Berkel
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
- University of Maastracht, Maastracht, The Netherlands
| | - Erik A. L. Biessen
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
- University of Maastracht, Maastracht, The Netherlands
| | - Richard W. Moyer
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Alexandra R. Lucas
- Vascular Biology Research Group, Robarts' Research Institute, London, Canada
- Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, United States of America
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| |
Collapse
|
|
31
|
Adams V, Heiker JT, Höllriegel R, Beck EB, Woitek FJ, Erbs S, Blüher M, Stumvoll M, Beck-Sickinger AG, Schuler G, Linke A. Adiponectin promotes the migration of circulating angiogenic cells through p38-mediated induction of the CXCR4 receptor. Int J Cardiol 2012; 167:2039-46. [PMID: 22682478 DOI: 10.1016/j.ijcard.2012.05.056] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Revised: 04/09/2012] [Accepted: 05/11/2012] [Indexed: 01/21/2023]
Abstract
AIMS Adiponectin (adipo) and exercise training (ET) contribute to the maintenance of a normal vascular tone by influencing vascular NO bioavailability and concentration and function of circulating angiogenic cells (CAC). The molecular mechanisms are only partially understood. Aim of the present study was to elucidate the effects of adipo on CAC migration and the underlying signaling pathways. Furthermore, the impact of ET on adiponectin-mediated CAC migration was investigated. METHODS AND RESULTS CACs were isolated from peripheral blood and exposed to different adipo concentrations. Adipo (5μg/ml) enhanced the ability of CACs to migrate following an SDF-1 gradient by 345%. This was associated with a significant increase in CXCR4 expression on the surface of CACs as compared to control (10.1 ± 1.5 vs. 33.2 ± 4.5% CXCR4 positive cells, p<0.05). Adiponectin-induced CAC migration and CXCR4-upregulation were mediated through adipo-receptor 1 (AdipoR1) and blocked by an inhibitor of PI3-kinase, p38MAP kinase and NFκb. Adipo-stimulated migration of CACs, CXCR4 expression and p38MAPK-activation is impaired in patients with coronary artery disease (CAD). ET over 4 weeks partially corrects adiponectin-stimulated CAC migration and CXCR4 expression in patients with CAD (n=10). No change was observed in the control group (n=10). CONCLUSION Adipo improves the migratory capacity of CACs in response to SDF1, partially through an upregulation of CXCR4. This is mediated through a pathway that involves binding of adipo to the AdipoR1 and subsequent PI3kinase/p38MAPK/ NFκb activation. In addition ET corrects the adiponectin responsiveness of CACs, and thereby might promote endogenous repair of damaged endothelium.
Collapse
Affiliation(s)
- Volker Adams
- Department of Internal Medicine/Cardiology, University Leipzig, Heart Center, Leipzig, Germany
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Xing YL, Zhou Z, Agula, Zhong ZY, Ma YJ, Zhao YL, Xiao XH, Wang SQ. Protocatechuic Aldehyde Inhibits Lipopolysaccharide-induced Human Umbilical Vein Endothelial Cell Apoptosis via Regulation of Caspase-3. Phytother Res 2012; 26:1334-41. [PMID: 22298410 DOI: 10.1002/ptr.3720] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 09/04/2011] [Accepted: 11/02/2011] [Indexed: 11/07/2022]
Affiliation(s)
- Ya-Ling Xing
- Beijing Institute of Radiation Medicine; 27 Taiping Road, Haidian District; Beijing; 100850; China
| | - Zhe Zhou
- Beijing Institute of Radiation Medicine; 27 Taiping Road, Haidian District; Beijing; 100850; China
| | - Agula
- Beijing Institute of Radiation Medicine; 27 Taiping Road, Haidian District; Beijing; 100850; China
| | - Zhi-Yin Zhong
- Beijing Institute of Radiation Medicine; 27 Taiping Road, Haidian District; Beijing; 100850; China
| | - Yong-Jie Ma
- Beijing Institute of Radiation Medicine; 27 Taiping Road, Haidian District; Beijing; 100850; China
| | | | | | | |
Collapse
|
|
33
|
Schuchardt M, Tölle M, Prüfer J, van der Giet M. Pharmacological relevance and potential of sphingosine 1-phosphate in the vascular system. Br J Pharmacol 2011; 163:1140-62. [PMID: 21309759 DOI: 10.1111/j.1476-5381.2011.01260.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Sphingosine-1-phosphate (S1P) was identified as a crucial molecule for regulating immune responses, inflammatory processes as well as influencing the cardiovascular system. S1P mediates differentiation, proliferation and migration during vascular development and homoeostasis. S1P is a naturally occurring lipid metabolite and is present in human blood in nanomolar concentrations. S1P is not only involved in physiological but also in pathophysiological processes. Therefore, this complex signalling system is potentially interesting for pharmacological intervention. Modulation of the system might influence inflammatory, angiogenic or vasoregulatory processes. S1P activates G-protein coupled receptors, namely S1P(1-5) , whereas only S1P(1-3) is present in vascular cells. S1P can also act as an intracellular signalling molecule. This review highlights the pharmacological potential of S1P signalling in the vascular system by giving an overview of S1P-mediated processes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). After a short summary of S1P metabolism and signalling pathways, the role of S1P in EC and VSMC proliferation and migration, the cause of relaxation and constriction of arterial blood vessels, the protective functions on endothelial apoptosis, as well as the regulatory function in leukocyte adhesion and inflammatory responses are summarized. This is followed by a detailed description of currently known pharmacological agonists and antagonists as new tools for mediating S1P signalling in the vasculature. The variety of effects influenced by S1P provides plenty of therapeutic targets currently under investigation for potential pharmacological intervention.
Collapse
Affiliation(s)
- Mirjam Schuchardt
- Charité- Universitätsmedizin Berlin, CharitéCentrum 10, Department of Nephrology, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, Germany
| | | | | | | |
Collapse
|
|
34
|
Heo KS, Fujiwara K, Abe JI. Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction. Circ J 2011; 75:2722-30. [PMID: 22076424 DOI: 10.1253/circj.cj-11-1124] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Emerging evidence is revealing the different roles of steady laminar flow (s-flow) and disturbed flow (d-flow) in the regulation of the vascular endothelium. s-flow is atheroprotective while d-flow creates an atheroprone environment. Most recently, we found unique atheroprone signals, which involve protein kinase C (PKC)ζ activation, elicited by d-flow. We and others have defined a novel role for PKCζ as a shared mediator for tumor necrosis factor alpha (TNF alpha) and d-flow, which cause pro-inflammatory and pro-apoptotic events in endothelial cells (ECs) in the atheroprone environment. Under such conditions, ONOO(-) formation is increased in a d-flow-mediated PKCζ-dependent manner. Here, we propose a new signaling pathway involving d-flow-induced EC inflammation via PKCζ-ERK5 interaction-mediated downregulation of KLF2/eNOS stability, which leads to PKCζ-mediated p53-SUMOylation and EC apoptosis. In addition, we highlight several mechanisms contributing to endothelial dysfunction, focusing on the relations between flow patterns and activation of reactive oxygen species generating enzymes.
Collapse
Affiliation(s)
- Kyung-Sun Heo
- Aab Cardiovascular Research Institute, University of Rochester, NY, USA
| | | | | |
Collapse
|
|
35
|
Afridi HI, Kazi TG, Kazi N, Kandhro GA, Baig JA, Shah AQ, Jamali MK, Arain MB, Wadhwa SK, Khan S, Kolachi NF, Shah F. Chromium and manganese levels in biological samples of Pakistani myocardial infarction patients at different stages as related to controls. Biol Trace Elem Res 2011; 142:259-73. [PMID: 20652649 DOI: 10.1007/s12011-010-8773-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2010] [Accepted: 07/07/2010] [Indexed: 10/19/2022]
Abstract
It has been speculated that trace elements may play a role in the pathogenesis of heart diseases In the present study, we aimed to access the levels of chromium (Cr) and manganese (Mn) in biological samples (whole blood, urine, and scalp hair) of myocardial infarction (MI) patients of both gender age ranged (45-60 years) at first, second, and third heart attack (n = 130), hospitalized in cardiac ward of National Hospital of Hyderabad city (Pakistan). For comparison, healthy age-matched referent subjects (n = 61), of both gender were also selected. The Cr and Mn in biological samples were measured by electrothermal atomic absorption spectrometry, prior to microwave-assisted acid digestion. The validity of the methodology was checked by the biological certified reference materials. During this study, 78% of 32 registered patients of third MI attack (aged >50 years) were died. In these subjects the concentration of Cr and Mn were decreased by 24.7% and 19.8% in scalp hair, while in blood samples 17.9% and 12.4%, respectively, as compared to those who tolerated third MI attack (p = 0.063). Although these data do not prove a causal relationship, these results are consistent with the hypothesis that heart disease may cause deficiencies of certain essential trace elements. The excretion levels of Cr and Mn in urine samples of first MCI were higher than controls at p values (0.029 and 0.011), respectively, whereas the excretion rates of both elements were further enhance after second myocardial infarction attack. The Cr and Mn concentration was inversely associated with the risk of myocardial infarction attacks in both genders. These results add to an increasing body of evidence that, Cr and Mn are importance for cardiovascular health.
Collapse
Affiliation(s)
- Hassan Imran Afridi
- National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080, Pakistan.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Okawada M, Koga H, Larsen SD, Showalter HD, Turbiak AJ, Jin X, Lucas PC, Lipka E, Hillfinger J, Kim JS, Teitelbaum DH. Use of enterally delivered angiotensin II type Ia receptor antagonists to reduce the severity of colitis. Dig Dis Sci 2011; 56:2553-65. [PMID: 21399927 PMCID: PMC3163034 DOI: 10.1007/s10620-011-1651-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Accepted: 02/16/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Renin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia receptor antagonists use, we hypothesized that use of angiotensin II type Ia receptor antagonists compounds which lack cell membrane permeability, and thus enteric absorption, would allow for direct enteral delivery at far higher concentrations than would be tolerated systemically, yet retain efficacy. METHODS Based on the structure of the angiotensin II type Ia receptor antagonist losartan, deschloro-losartan was synthesized, which has extremely poor cell membrane permeability. Angiotensin II type Ia receptor antagonist efficacy was evaluated by determining the ability to block NF-κB activation in vitro. Dextran sodium sulfate colitis was induced in mice and angiotensin II type Ia receptor antagonist efficacy delivered transanally was assessed. RESULTS In vitro, deschloro-losartan demonstrated near equal angiotensin II type Ia receptor blockade compared to losartan as well as another angiotensin II type Ia receptor antagonist, candesartan. In the dextran sodium sulfate model, each compound significantly improved clinical and histologic scores and epithelial cell apoptosis. Abundance of TNF-α, IL-1β, and IL6 mRNA were significantly decreased with each compound. In vitro and in vivo intestinal drug absorption, as well as measures of blood pressure and mucosal and colonic blood flow, showed significantly lower uptake of deschloro-losartan compared to losartan and candesartan. CONCLUSIONS This study demonstrated efficacy of high-dose angiotensin II type Ia receptor antagonists in this colitis model. We postulate that a specially designed angiotensin II type Ia receptor antagonist with poor oral absorption may have great potential as a new therapeutic agent for inflammatory bowel disease in the future.
Collapse
Affiliation(s)
- Manabu Okawada
- Section of Pediatric Surgery, Department of Surgery, The University of Michigan Medical School, Mott Children’s Hospital, F3970, Ann Arbor, MI 48109-0245, USA
| | - Hiroyuki Koga
- Section of Pediatric Surgery, Department of Surgery, The University of Michigan Medical School, Mott Children’s Hospital, F3970, Ann Arbor, MI 48109-0245, USA
| | - Scott D. Larsen
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA
| | - Hollis D. Showalter
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA
| | - Anjanette J. Turbiak
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA
| | - Xiaohong Jin
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Peter C. Lucas
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Elke Lipka
- Therapeutic Systems Research Laboratories, Inc, Ann Arbor, MI 48108, USA
| | - John Hillfinger
- Therapeutic Systems Research Laboratories, Inc, Ann Arbor, MI 48108, USA
| | - Jae Seung Kim
- Therapeutic Systems Research Laboratories, Inc, Ann Arbor, MI 48108, USA
| | - Daniel H. Teitelbaum
- Section of Pediatric Surgery, Department of Surgery, The University of Michigan Medical School, Mott Children’s Hospital, F3970, Ann Arbor, MI 48109-0245, USA
| |
Collapse
|
|
37
|
Hörmann M, Mey L, Kharip Z, Hildenberg A, Nemeth K, Heidt M, Renz H, Al-Fakhri N. Vascular endothelial growth factor confers endothelial resistance to apoptosis through poly(ADP-ribose) polymerase. J Thromb Haemost 2011; 9:1391-403. [PMID: 21605336 DOI: 10.1111/j.1538-7836.2011.04368.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) inhibits the endothelial apoptosis that is induced by caspases during vascular remodeling; however, the underlying mechanisms have not been completely elucidated. OBJECTIVES We hypothesized that VEGF upregulates poly(ADP-ribose) polymerase-1 (PARP) as a caspase mediator, and sought to investigate the link between apoptosis inhibition by VEGF and PARP regulation in the human vasculature. METHODS Human endothelial cells (primary cells, macrovascular/microvascular lines) were incubated with 100 pg mL(-1) to 1 μg mL(-1) VEGF-A(165) in the absence or presence of PARP small interfering RNA (siRNA). Apoptosis induced by integrin inhibition was measured by flow cytometry, trypan blue exclusion, and nuclear morphology. PARP expression and activity were determined by real-time RT-PCR, Western blot, and ribosylation assay. VEGF receptors and signal transduction were analyzed by inhibitor experiments, enzyme assays, western blot, and immunofluorescence microscopy. Immunohistochemistry was applied to a vascular culture model and to 24 atherosclerotic and 10 normal human arteries. RESULTS VEGF-A(165) induced resistance to apoptosis caused by caspase activation in endothelial cells in a time-dependent manner. VEGF, but not fibroblast growth factor-2 or transforming growth factor-β, time-dependently and dose-dependently induced PARP expression and activity, involving VEGF receptor-2 colocalized with neuropilin-1 as well as the signal transduction molecules c-Jun N-terminal kinase and Akt. The antiapoptotic effect of VEGF was abrogated by PARP siRNA. The relationship between local VEGF influence and endothelial PARP expression was confirmed in human arteries and the vascular culture model. CONCLUSIONS VEGF exerts its antiapoptotic effect on the endothelium through the regulation of PARP expression. PARP has been attributed an ambiguous role in apoptosis; here, we show that PARP promotes vascular endothelial integrity in VEGF-associated processes.
Collapse
Affiliation(s)
- M Hörmann
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University, Marburg, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Poitz DM, Augstein A, Weinert S, Braun-Dullaeus RC, Strasser RH, Schmeisser A. OxLDL and macrophage survival: essential and oxygen-independent involvement of the Hif-pathway. Basic Res Cardiol 2011; 106:761-72. [DOI: 10.1007/s00395-011-0186-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2010] [Revised: 04/17/2011] [Accepted: 04/26/2011] [Indexed: 01/11/2023]
|
|
39
|
Schutters K, Reutelingsperger C. Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis 2010; 15:1072-82. [PMID: 20440562 PMCID: PMC2929432 DOI: 10.1007/s10495-010-0503-y] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface.
Collapse
Affiliation(s)
- Kristof Schutters
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
| | | |
Collapse
|
|
40
|
Al-Mutairi M, Al-Harthi S, Cadalbert L, Plevin R. Over-expression of mitogen-activated protein kinase phosphatase-2 enhances adhesion molecule expression and protects against apoptosis in human endothelial cells. Br J Pharmacol 2010; 161:782-98. [PMID: 20860659 DOI: 10.1111/j.1476-5381.2010.00952.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND AND PURPOSE We assessed the effects of over-expressing the dual-specific phosphatase, mitogen-activated protein (MAP) kinase phosphatase-2 (MKP-2), in human umbilical vein endothelial cells (HUVECs) on inflammatory protein expression and apoptosis, two key features of endothelial dysfunction in disease. EXPERIMENTAL APPROACHES We infected HUVECs for 40 h with an adenoviral version of MKP-2 (Adv.MKP-2). Tumour necrosis factor (TNF)-α-stimulated phosphorylation of MAP kinase and protein expression was measured by Western blotting. Cellular apoptosis was assayed by FACS. KEY RESULTS Infection with Adv.MKP-2 selectively abolished TNF-α-mediated c-Jun-N-terminal kinase (JNK) activation and had little effect upon extracellular signal-regulated kinase or p38 MAP kinase. Adv.MKP-2 abolished COX-2 expression, while induction of the endothelial cell adhesion molecules, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), two NFκB-dependent proteins, was not affected. However, when ICAM and VCAM expression was partly reduced by blockade of the NFκB pathway, Adv.MKP-2 was able to reverse this inhibition. This correlated with enhanced TNF-α-induced loss of the inhibitor of κB (IκB)α loss, a marker of NFκB activation. TNF-α in combination with NFκB blockade also increased HUVEC apoptosis; this was significantly reversed by Adv.MKP-2. Protein markers of cellular damage and apoptosis, H2AX phosphorylation and caspase-3 cleavage, were also reversed by MKP-2 over-expression. CONCLUSIONS AND IMPLICATIONS Over-expression of MKP-2 had different effects upon the expression of inflammatory proteins due to a reciprocal effect upon JNK and NFκB signalling, and also prevented TNF-α-mediated endothelial cell death. These properties may make Adv.MKP-2 a potentially useful future therapy in cardiovascular diseases where endothelial dysfunction is a feature.
Collapse
Affiliation(s)
- Mashael Al-Mutairi
- Division of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow, UK
| | | | | | | |
Collapse
|
|
41
|
Koh SL, Ager EI, Christophi C. Liver regeneration and tumour stimulation: implications of the renin-angiotensin system. Liver Int 2010; 30:1414-26. [PMID: 20633100 DOI: 10.1111/j.1478-3231.2010.02306.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver resection is the most effective treatment for primary liver tumours and metastasis to the liver, and remains the only potentially long-term curative therapy for patients with colorectal cancer (CRC) liver metastases. Nevertheless, there is a significant incidence of tumour recurrence following liver resection. Cellular and molecular changes resulting from resection and the subsequent liver regeneration process may influence the kinetics of tumour growth, contributing to recurrence. Although commonly associated with the systemic homeostasis of blood pressure, fluid and electrolyte, the renin-angiotensin system (RAS) has recently been shown to play a role in regulating cell proliferation, apoptosis and angiogenesis in local organs as well as in malignancies. An electronic search of the English literature on the role of the RAS in liver regeneration and tumourigenesis was performed using PubMed, with additional relevant articles sourced from reference lists. Studies have shown that the blockade of the RAS pathway stimulates liver regeneration and inhibits tumour progression. An understanding of the role of RAS in liver regeneration and tumourigenesis may enable alternative strategies to improve patient outcome and survival after liver resection. This review will discuss the role of the RAS in liver regeneration and in tumour recurrence post-liver resection. The potential of the RAS as a novel therapeutic target for CRC liver metastases patients undergoing liver resection will be outlined.
Collapse
Affiliation(s)
- Shir Lin Koh
- Austin Health, Department of Surgery, The University of Melbourne, Heidelberg, Vic., Australia.
| | | | | |
Collapse
|
|
42
|
Zhang Z, Li W, Sun D, Zhao L, Zhang R, Wang Y, Zhou X, Wang H, Cao F. Toll-like receptor 4 signaling in dysfunction of cardiac microvascular endothelial cells under hypoxia/reoxygenation. Inflamm Res 2010; 60:37-45. [PMID: 20652722 DOI: 10.1007/s00011-010-0232-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Revised: 04/06/2010] [Accepted: 06/28/2010] [Indexed: 12/28/2022] Open
Affiliation(s)
- Zheng Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032 Shaanxi, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Chambliss KL, Wu Q, Oltmann S, Konaniah ES, Umetani M, Korach KS, Thomas GD, Mineo C, Yuhanna IS, Kim SH, Madak-Erdogan Z, Maggi A, Dineen SP, Roland CL, Hui DY, Brekken RA, Katzenellenbogen JA, Katzenellenbogen BS, Shaul PW. Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. J Clin Invest 2010; 120:2319-30. [PMID: 20577047 DOI: 10.1172/jci38291] [Citation(s) in RCA: 205] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Accepted: 04/14/2010] [Indexed: 12/29/2022] Open
Abstract
Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERalpha, direct ERalpha-Galphai interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERalpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.
Collapse
Affiliation(s)
- Ken L Chambliss
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Schutters K, Reutelingsperger C. Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis 2010. [PMID: 20440562 DOI: 10.1007/s10495-010�0503-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface.
Collapse
Affiliation(s)
- Kristof Schutters
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
| | | |
Collapse
|
|
45
|
Krieglstein J, Kewitz T, Kirchhefer U, Hofnagel O, Weissen-Plenz G, Reinbold M, Klumpp S. Damage of guinea pig heart and arteries by a trioleate-enriched diet and of cultured cardiomyocytes by oleic acid. PLoS One 2010; 5:e9561. [PMID: 20221399 PMCID: PMC2833202 DOI: 10.1371/journal.pone.0009561] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2009] [Accepted: 02/15/2010] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Mono-unsaturated fatty acids (MUFAs) like oleic acid have been shown to cause apoptosis of cultured endothelial cells by activating protein phosphatase type 2C alpha and beta (PP2C). The question arises whether damage of endothelial or other cells could be observed in intact animals fed with a trioleate-enriched diet. METHODOLOGY/PRINCIPAL FINDINGS Dunkin-Hartley guinea pigs were fed with a trioleate-enriched diet for 5 months. Advanced atherosclerotic changes of the aorta and the coronary arteries could not be seen but the arteries appeared in a pre-atherosclerotic stage of vascular remodelling. However, the weight and size of the hearts were lower than in controls and the number of apoptotic myocytes increased in the hearts of trioleate-fed animals. To confirm the idea that oleic acid may have caused this apoptosis by activation of PP2C, cultured cardiomyocytes from guinea pigs and mice were treated with various lipids. It was demonstrable that oleic acid dose-dependently caused apoptosis of cardiomyocytes from both species, yet, similar to previous experiments with cultured neurons and endothelial cells, stearic acid, elaidic acid and oleic acid methylester did not. The apoptotic effect caused by oleic acid was diminished when PP2C alpha and beta were downregulated by siRNA showing that PP2C was causally involved in apoptosis caused by oleic acid. CONCLUSIONS/SIGNIFICANCE The glycerol trioleate diet given to guinea pigs for 5 months did not cause marked atherosclerosis but clearly damaged the hearts by activating PP2C alpha and beta. The diet used with 24% (wt/wt) glycerol trioleate is not comparable to human diets. The detrimental role of MUFAs for guinea pig heart tissue in vivo is shown for the first time. Whether it is true for humans remains to be shown.
Collapse
Affiliation(s)
- Josef Krieglstein
- Institut für Pharmazeutische und Medizinische Chemie, Westfaelische Wilhelms-Universitaet, Muenster, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Schmidt-Lucke C, Fichtlscherer S, Rössig L, Kämper U, Dimmeler S. Improvement of endothelial damage and regeneration indexes in patients with coronary artery disease after 4 weeks of statin therapy. Atherosclerosis 2010; 211:249-54. [PMID: 20211468 DOI: 10.1016/j.atherosclerosis.2010.02.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Revised: 01/22/2010] [Accepted: 02/04/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND In patients with coronary artery disease (CAD), higher numbers of circulating endothelial progenitor cells (EPC) favourably influence clinical outcome. Controversially, increased apoptosis of endothelial cells (EC) may reflect vascular damage. Statins have been shown to improve vascular damage and enhance EPC function and numbers. The availability of ezetimibe, a potent novel cholesterol absorption inhibitor, allows to distinguish between lipid-lowering and pleiotropic properties of statins. METHODS AND FINDINGS 43 patients with CAD were assigned to receive either: de novo atorvastatin (group A; n=17), ezetimibe as add-on to chronic statin therapy (group B; n=14), or dose escalation of atorvastatin (group C; n=12) over 4 weeks. Circulating apoptotic EC (CD45-CD146+vWF+Annexin-V+) and EPC (CD34+KDR+) were quantified using flow cytometry. LDL cholesterol levels were significantly reduced in all treatment arms. Both statin groups, group A and group C, showed significantly reduced circulating apoptotic EC by 50% each (p<0.01). On the other hand, there was a significant doubling in the numbers of circulating EPC in group A and group C (p<0.005, each). Consequently, the endothelial damage-index calculated from numbers of circulating apoptotic mature EC related to EPC numbers, was improved in group A by 79% (p<0.01) and in group C by 70% (p<0.05). In contrast, sole LDL reduction by ezetimibe exerted no effect on any of the different circulating endothelial cell types. CONCLUSION Thus, the improvement in numbers of EPC and reduction of mature apoptotic EC after 4 weeks of statin therapy, document a novel pleiotropic effect of statin therapy in patients with CAD.
Collapse
|
|
47
|
Kansanen E, Jyrkkänen HK, Volger OL, Leinonen H, Kivelä AM, Häkkinen SK, Woodcock SR, Schopfer FJ, Horrevoets AJ, Ylä-Herttuala S, Freeman BA, Levonen AL. Nrf2-dependent and -independent responses to nitro-fatty acids in human endothelial cells: identification of heat shock response as the major pathway activated by nitro-oleic acid. J Biol Chem 2009; 284:33233-41. [PMID: 19808663 PMCID: PMC2785166 DOI: 10.1074/jbc.m109.064873] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2009] [Revised: 10/02/2009] [Indexed: 01/23/2023] Open
Abstract
Electrophilic fatty acid derivatives, including nitrolinoleic acid and nitro-oleic acid (OA-NO(2)), can mediate anti-inflammatory and pro-survival signaling reactions. The transcription factor Nrf2, activated by electrophilic fatty acids, suppresses redox-sensitive pro-inflammatory gene expression and protects against vascular endothelial oxidative injury. It was therefore postulated that activation of Nrf2 by OA-NO(2) accounts in part for its anti-inflammatory actions, motivating the characterization of Nrf2-dependent and -independent effects of OA-NO(2) on gene expression using genome-wide transcriptional profiling. Control and Nrf2-small interfering RNA-transfected human endothelial cells were treated with vehicle, oleic acid, or OA-NO(2), and differential gene expression profiles were determined. Although OA-NO(2) significantly induced the expression of Nrf2-dependent genes, including heme oxygenase-1 and glutamate-cysteine ligase modifier subunit, the majority of OA-NO(2)-regulated genes were regulated by Nrf2-independent pathways. Moreover, gene set enrichment analysis revealed that the heat shock response is the major pathway activated by OA-NO(2), with robust induction of a number of heat shock genes regulated by the heat shock transcription factor. Inasmuch as the heat shock response mediates anti-inflammatory and cytoprotective actions, this mechanism is proposed to contribute to the protective cell signaling functions of nitro-fatty acids and other electrophilic fatty acid derivatives.
Collapse
Affiliation(s)
- Emilia Kansanen
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| | - Henna-Kaisa Jyrkkänen
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| | - Oscar L. Volger
- the Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, The Netherlands, and
| | - Hanna Leinonen
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| | - Annukka M. Kivelä
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| | - Sanna-Kaisa Häkkinen
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| | - Steven R. Woodcock
- the Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
| | - Francisco J. Schopfer
- the Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
| | - Anton J. Horrevoets
- the Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, The Netherlands, and
| | - Seppo Ylä-Herttuala
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| | - Bruce A. Freeman
- the Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
| | - Anna-Liisa Levonen
- From the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland
| |
Collapse
|
|
48
|
Petersen TH, Hitchcock T, Muto A, Calle EA, Zhao L, Gong Z, Gui L, Dardik A, Bowles DE, Counter CM, Niklason LE. Utility of telomerase-pot1 fusion protein in vascular tissue engineering. Cell Transplant 2009; 19:79-87. [PMID: 19878625 DOI: 10.3727/096368909x478650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
While advances in regenerative medicine and vascular tissue engineering have been substantial in recent years, important stumbling blocks remain. In particular, the limited life span of differentiated cells that are harvested from elderly human donors is an important limitation in many areas of regenerative medicine. Recently, a mutant of the human telomerase reverse transcriptase enzyme (TERT) was described, which is highly processive and elongates telomeres more rapidly than conventional telomerase. This mutant, called pot1-TERT, is a chimeric fusion between the DNA binding protein pot1 and TERT. Because pot1-TERT is highly processive, it is possible that transient delivery of this transgene to cells that are utilized in regenerative medicine applications may elongate telomeres and extend cellular life span while avoiding risks that are associated with retroviral or lentiviral vectors. In the present study, adenoviral delivery of pot1-TERT resulted in transient reconstitution of telomerase activity in human smooth muscle cells, as demonstrated by telomeric repeat amplification protocol (TRAP). In addition, human engineered vessels that were cultured using pot1-TERT-expressing cells had greater collagen content and somewhat better performance in vivo than control grafts. Hence, transient delivery of pot1-TERT to elderly human cells may be useful for increasing cellular life span and improving the functional characteristics of resultant tissue-engineered constructs.
Collapse
Affiliation(s)
- Thomas H Petersen
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease. Basic Res Cardiol 2009; 102:565-71. [PMID: 17932708 DOI: 10.1007/s00395-007-0680-1] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Revised: 09/10/2007] [Accepted: 09/13/2007] [Indexed: 12/22/2022]
Abstract
Endothelial progenitor cells (EPC) predict morbidity and mortality in patients at cardiovascular risk.Patients with low EPC counts and impaired endothelial colony forming activity have a higher incidence for cardiovascular events compared to patients with high EPC counts and favorable colony forming activity. The pathophysiological basis for this finding may be an insufficient endothelial cell repair by EPC.We postulate that EPC influence coronary endothelial function which itself is relevant for the outcome of patients at cardiovascular risk. To test this hypothesis in humans, endothelial function was invasively assessed in 90 patients with coronary heart disease by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry of mononuclear cells isolated from peripheral blood was performed to assess CD133(+) or CD34(+)/KDR(+) EPC. EPC function was assessed ex vivo by determination of endothelial colony forming units. Low EPC number as well as impaired endothelial colony forming activity correlated with severely impaired coronary endothelial function in univariate analysis. Multivariate analysis revealed that only the number of EPC predicts severe endothelial dysfunction independent of classical cardiovascular risk factors. Endothelial function closely correlates with the number of circulating EPC providing new mechanistic insights and options for risk assessment in patients with coronary heart disease.
Collapse
|
|
50
|
Wei Y, Whaley-Connell AT, Habibi J, Rehmer J, Rehmer N, Patel K, Hayden M, DeMarco V, Ferrario CM, Ibdah JA, Sowers JR. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension 2008; 53:158-65. [PMID: 19114643 DOI: 10.1161/hypertensionaha.108.121954] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine(473) phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine(136) and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects.
Collapse
Affiliation(s)
- Yongzhong Wei
- Department of Medicine, Diabetes and Cardiovascular Center of Excellence, University of Missouri-Columbia, Columbia, MO 65212, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|