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Huang Y, Xie X, Huang G, Hong X, Lu W, Fu W, Wang L. CXCL8 upregulation mediates inflammatory cell infiltration and accelerates abdominal aortic aneurysm progression. Sci Prog 2025; 108:368504251328754. [PMID: 40129393 PMCID: PMC11938877 DOI: 10.1177/00368504251328754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
OBJECTIVE To explore abdominal aortic aneurysm (AAA) pathogenesis and identify early diagnostic markers, providing a theoretical basis for novel preventive and therapeutic strategies. METHODS Gene expression profiles were retrieved from the Gene Expression Omnibus database (datasets: GSE7084, GSE47472, and GSE57691) comprising messenger RNA data from the aortic samples of 69 patients with AAA and 25 non-AAA controls. Data were merged and normalized; bioinformatics analysis was conducted on upregulated differentially expressed genes. RESULTS C-X-C motif chemokine ligand 8 (CXCL8) was prominently involved in regulating the chemokine signaling pathway. CXCL8 expression was significantly higher in the aortic walls of patients with AAA than that of controls. NLRP3, interleukin (IL)-18, and IL-1β expression levels were upregulated in patients with AAA and positively correlated with CXCL8 expression. CXCL8 may directly or indirectly interact with NLRP3. CONCLUSIONS CXCL8 was upregulated in patients with AAA and induced inflammatory cell infiltration and cytokine secretion. CXCL8-induced NLRP3 inflammasome regulation triggered pyroptosis in vascular smooth muscle cells, exacerbating inflammation and tissue damage in the aortic wall. This degeneration of the aortic media accelerated AAA progression.
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Affiliation(s)
- Yulong Huang
- Department of Vascular Surgery, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
| | - Xinsheng Xie
- Department of Vascular Surgery, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
| | - Guoqiang Huang
- Department of Radiology, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
| | - Xiang Hong
- Department of Vascular Surgery, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
| | - Weifeng Lu
- Department of Vascular Surgery, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
| | - Weiguo Fu
- Department of Vascular Surgery, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lixin Wang
- Department of Vascular Surgery, Xiamen Branch of Zhongshan Hospital, Fudan University, Xiamen, China
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Dutka M, Zimmer K, Ćwiertnia M, Ilczak T, Bobiński R. The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol. Heart Fail Rev 2024; 29:917-937. [PMID: 38886277 PMCID: PMC11306431 DOI: 10.1007/s10741-024-10409-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.
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Affiliation(s)
- Mieczysław Dutka
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland.
| | - Karolina Zimmer
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
| | - Michał Ćwiertnia
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Tomasz Ilczak
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Rafał Bobiński
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
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Barkhordarian M, Tran HHV, Menon A, Pulipaka SP, Aguilar IK, Fuertes A, Dey S, Chacko AA, Sethi T, Bangolo A, Weissman S. Innovation in pathogenesis and management of aortic aneurysm. World J Exp Med 2024; 14:91408. [PMID: 38948412 PMCID: PMC11212750 DOI: 10.5493/wjem.v14.i2.91408] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/04/2024] [Accepted: 03/18/2024] [Indexed: 06/19/2024] Open
Abstract
Aortic aneurysm (AA) refers to the persistent dilatation of the aorta, exceeding three centimeters. Investigating the pathophysiology of this condition is important for its prevention and management, given its responsibility for more than 25000 deaths in the United States. AAs are classified based on their location or morphology. various pathophysiologic pathways including inflammation, the immune system and atherosclerosis have been implicated in its development. Inflammatory markers such as transforming growth factor β, interleukin-1β, tumor necrosis factor-α, matrix metalloproteinase-2 and many more may contribute to this phenomenon. Several genetic disorders such as Marfan syndrome, Ehler-Danlos syndrome and Loeys-Dietz syndrome have also been associated with this disease. Recent years has seen the investigation of novel management of AA, exploring the implication of different immune suppressors, the role of radiation in shrinkage and prevention, as well as minimally invasive and newly hypothesized surgical methods. In this narrative review, we aim to present the new contributing factors involved in pathophysiology of AA. We also highlighted the novel management methods that have demonstrated promising benefits in clinical outcomes of the AA.
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Affiliation(s)
- Maryam Barkhordarian
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Hadrian Hoang-Vu Tran
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Aiswarya Menon
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Sai Priyanka Pulipaka
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Izage Kianifar Aguilar
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Axel Fuertes
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shraboni Dey
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Angel Ann Chacko
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Tanni Sethi
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Ayrton Bangolo
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Simcha Weissman
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
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Liu C, Guo X, Zhang X. Modulation of atherosclerosis-related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives. Phytother Res 2024; 38:2892-2930. [PMID: 38577989 DOI: 10.1002/ptr.8203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/06/2024]
Abstract
Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), NF-E2-related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator-activated receptor (PPAR), nucleotide oligo-structural domain-like receptor thermoprotein structural domain-associated protein 3 (NLRP3), silencing information regulator 2-associated enzyme 1 (Sirt1), nuclear transcription factor-κB (NF-κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor-β (TGF-β), and Janus kinase-signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high-intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.
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Affiliation(s)
- Changxing Liu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xinyi Guo
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xulong Zhang
- Shaanxi Provincial Rehabilitation Hospital, Xi'an, China
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Pi S, Xiong S, Yuan Y, Deng H. The Role of Inflammasome in Abdominal Aortic Aneurysm and Its Potential Drugs. Int J Mol Sci 2024; 25:5001. [PMID: 38732221 PMCID: PMC11084561 DOI: 10.3390/ijms25095001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic inflammatory response is the core process in AAA occurrence and development. Inflammasome, a multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory cytokines like interleukin (IL)-1β and IL-18, and thus plays a pivotal role in inflammation regulation. Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods.
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Affiliation(s)
- Suyu Pi
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.P.); (S.X.); (Y.Y.)
- Aortic Abdominal Aneurysm (AAA) Translational Medicine Research Center of Hubei Province, Wuhan 430060, China
| | - Sizheng Xiong
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.P.); (S.X.); (Y.Y.)
- Aortic Abdominal Aneurysm (AAA) Translational Medicine Research Center of Hubei Province, Wuhan 430060, China
| | - Yan Yuan
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.P.); (S.X.); (Y.Y.)
- Aortic Abdominal Aneurysm (AAA) Translational Medicine Research Center of Hubei Province, Wuhan 430060, China
| | - Hongping Deng
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.P.); (S.X.); (Y.Y.)
- Aortic Abdominal Aneurysm (AAA) Translational Medicine Research Center of Hubei Province, Wuhan 430060, China
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Gu X, Yu Z, Qian T, Jin Y, Xu G, Li J, Gu J, Li M, Tao K. Transcriptomic analysis identifies the shared diagnostic biomarkers and immune relationship between Atherosclerosis and abdominal aortic aneurysm based on fatty acid metabolism gene set. Front Mol Biosci 2024; 11:1365447. [PMID: 38660376 PMCID: PMC11040089 DOI: 10.3389/fmolb.2024.1365447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/21/2024] [Indexed: 04/26/2024] Open
Abstract
Background Epidemiological research has demonstrated that there is a connection between lipid metabolism disorder and an increased risk of developing arteriosclerosis (AS) and abdominal aortic aneurysm (AAA). However, the precise relationship between lipid metabolism, AS, and AAA is still not fully understood. The objective of this study was to examine the pathways and potential fatty acid metabolism-related genes (FRGs) that are shared between AS and AAA. Methods AS- and AAA-associated datasets were retrieved from the Gene Expression Omnibus (GEO) database, and the limma package was utilized to identify differentially expressed FRGs (DFRGs) common to both AS and AAA patients. Functional enrichment analysis was conducted on the (DFRGs), and a protein-protein interaction (PPI) network was established. The selection of signature genes was performed through the utilization of least absolute shrinkage and selection operator (LASSO) regression and random forest (RF). Subsequently, a nomogram was developed using the results of the screening process, and the crucial genes were validated in two separate external datasets (GSE28829 and GSE17901) as well as clinical samples. In the end, single-sample gene set enrichment analysis (ssGSEA) was utilized to assess the immune cell patterns in both AS and AAA. Additionally, the correlation between key crosstalk genes and immune cell was evaluated. Results In comparison to control group, both AS and AAA patients exhibited a decrease in fatty acid metabolism score. We found 40 DFRGs overlapping in AS and AAA, with lipid and amino acid metabolism critical in their pathogenesis. PCBD1, ACADL, MGLL, BCKDHB, and IDH3G were identified as signature genes connecting AS and AAA. Their expression levels were confirmed in validation datasets and clinical samples. The analysis of immune infiltration showed that neutrophils, NK CD56dim cells, and Tem cells are important in AS and AAA development. Correlation analysis suggested that these signature genes may be involved in immune cell infiltration. Conclusion The fatty acid metabolism pathway appears to be linked to the development of both AS and AAA. Furthermore, PCBD1, ACADL, MGLL, BCKDHB, and IDH3G have the potential to serve as diagnostic markers for patients with AS complicated by AAA.
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Affiliation(s)
- Xuefeng Gu
- Department of General Surgery, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, China
| | - Zhongxian Yu
- Department of General Surgery, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, China
| | - Tianwei Qian
- Department of General Surgery, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, China
| | - Yiqi Jin
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China
| | - Guoxiong Xu
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China
| | - Jiang Li
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China
| | - Jianfeng Gu
- Department of General Surgery, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, China
| | - Ming Li
- Department of General Surgery, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, China
| | - Ke Tao
- Department of General Surgery, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, China
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Sulistyowati E, Huang SE, Cheng TL, Chao YY, Li CY, Chang CW, Lin MX, Lin MC, Yeh JL. Vasculoprotective Potential of Baicalein in Angiotensin II-Infused Abdominal Aortic Aneurysms through Inhibiting Inflammation and Oxidative Stress. Int J Mol Sci 2023; 24:16004. [PMID: 37958985 PMCID: PMC10647516 DOI: 10.3390/ijms242116004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/26/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
Aortic wall inflammation, abnormal oxidative stress and progressive degradation of extracellular matrix proteins are the main characteristics of abdominal aortic aneurysms (AAAs). The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome dysregulation plays a crucial role in aortic damage and disease progression. The first aim of this study was to examine the effect of baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one) on AAA formation in apolipoprotein E-deficient (ApoE-/-) mice. The second aim was to define whether baicalein attenuates aberrant vascular smooth muscle cell (VSMC) proliferation and inflammation in VSMC culture. For male ApoE-/- mice, a clinically relevant AAA model was randomly divided into four groups: saline infusion, baicalein intraperitoneal injection, Angiotensin II (Ang II) infusion and Ang II + baicalein. Twenty-seven days of treatment with baicalein markedly decreased Ang II-infused AAA incidence and aortic diameter, reduced collagen-fiber formation, preserved elastic structure and density and prevented smooth muscle cell contractile protein degradation. Baicalein inhibited rat VSMC proliferation and migration following the stimulation of VSMC cultures with Ang II while blocking the Ang II-inducible cell cycle progression from G0/G1 to the S phase in the synchronized cells. Cal-520 AM staining showed that baicalein decreased cellular calcium in Ang II-induced VSMCs; furthermore, a Western blot assay indicated that baicalein inhibited the expression of PCNA and significantly lowered levels of phospho-Akt and phospho-ERK, along with an increase in baicalein concentration in Ang II-induced VSMCs. Immunofluorescence staining showed that baicalein pretreatment reduced NF-κB nuclear translocation in Ang II-induced VSMCs and furthered the protein expressions of NLRP3 while ASC and caspase-1 were suppressed in a dose-dependent manner. Baicalein pretreatment upregulated Nrf2/HO-1 signaling in Ang II-induced VSMCs. Thus, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining showed that its reactive oxygen species (ROS) production decreased, along with the baicalein pretreatment. Our overall results indicate that baicalein could have therapeutic potential in preventing aneurysm development.
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Affiliation(s)
- Erna Sulistyowati
- Faculty of Medicine, University of Islam Malang, Malang City 65145, Indonesia;
| | - Shang-En Huang
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (S.-E.H.); (C.-W.C.); (M.-X.L.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Tsung-Lin Cheng
- Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- College of Professional Studies, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Yu-Ying Chao
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Chia-Yang Li
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Ching-Wen Chang
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (S.-E.H.); (C.-W.C.); (M.-X.L.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Meng-Xuan Lin
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (S.-E.H.); (C.-W.C.); (M.-X.L.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Ming-Chung Lin
- Department of Anesthesiology, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan 717, Taiwan
| | - Jwu-Lai Yeh
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (S.-E.H.); (C.-W.C.); (M.-X.L.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan
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Lin PK, Davis GE. Extracellular Matrix Remodeling in Vascular Disease: Defining Its Regulators and Pathological Influence. Arterioscler Thromb Vasc Biol 2023; 43:1599-1616. [PMID: 37409533 PMCID: PMC10527588 DOI: 10.1161/atvbaha.123.318237] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/23/2023] [Indexed: 07/07/2023]
Abstract
Because of structural and cellular differences (ie, degrees of matrix abundance and cross-linking, mural cell density, and adventitia), large and medium-sized vessels, in comparison to capillaries, react in a unique manner to stimuli that induce vascular disease. A stereotypical vascular injury response is ECM (extracellular matrix) remodeling that occurs particularly in larger vessels in response to injurious stimuli, such as elevated angiotensin II, hyperlipidemia, hyperglycemia, genetic deficiencies, inflammatory cell infiltration, or exposure to proinflammatory mediators. Even with substantial and prolonged vascular damage, large- and medium-sized arteries, persist, but become modified by (1) changes in vascular wall cellularity; (2) modifications in the differentiation status of endothelial cells, vascular smooth muscle cells, or adventitial stem cells (each can become activated); (3) infiltration of the vascular wall by various leukocyte types; (4) increased exposure to critical growth factors and proinflammatory mediators; and (5) marked changes in the vascular ECM, that remodels from a homeostatic, prodifferentiation ECM environment to matrices that instead promote tissue reparative responses. This latter ECM presents previously hidden matricryptic sites that bind integrins to signal vascular cells and infiltrating leukocytes (in coordination with other mediators) to proliferate, invade, secrete ECM-degrading proteinases, and deposit injury-induced matrices (predisposing to vessel wall fibrosis). In contrast, in response to similar stimuli, capillaries can undergo regression responses (rarefaction). In summary, we have described the molecular events controlling ECM remodeling in major vascular diseases as well as the differential responses of arteries versus capillaries to key mediators inducing vascular injury.
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Affiliation(s)
- Prisca K. Lin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL 33612
| | - George E. Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL 33612
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Yang X, Wang C, Zhu G, Guo Z, Fan L. METTL14/YTHDF1 axis-modified UCHL5 aggravates atherosclerosis by activating the NLRP3 inflammasome. Exp Cell Res 2023; 427:113587. [PMID: 37044315 DOI: 10.1016/j.yexcr.2023.113587] [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: 12/06/2022] [Revised: 03/28/2023] [Accepted: 04/04/2023] [Indexed: 04/14/2023]
Abstract
BACKGROUND Vascular smooth muscle cell (VSMC) phenotypic switching contributes to VSMC proliferation and migration in atherosclerosis (AS). Nevertheless, the regulatory mechanism of VSMC phenotypic switching during AS progression is unclear. Here, the role and regulatory mechanism of UCHL5 in VSMC phenotypic switching during AS progression were investigated. METHODS ApoE-/- mice were fed with high fat diet to establish AS model in vivo. VSMCs stimulated by ox-LDL were used as AS cellular model. VSMC proliferation and migration were examined by CCK8 assay and transwell assay, respectively. The levels of pro-inflammatory cytokines were assessed using ELISA. The interactions between METTL14/YTHDF1, UCHL5 and NLRP3 were analyzed using RIP and/or dual-luciferase reporter gene and/or Co-IP assays. NLRP3 ubiquitination was analyzed by ubiquitination analysis. RESULTS UCHL5 was significantly upregulated in AS patients and ox-LDL-treated VSMCs. UCHL5 silencing ameliorated plaque formation and vascular remodeling in vivo and suppressed ox-LDL-induced VSMC proliferation, migration, inflammation and phenotypic switching in vitro. Moreover, METTL14 could increase UCHL5 mRNA m6A level and promoted UCHL5 expression by recruiting YTHDF1. Moreover, UCHL5 overexpression enhanced protein stability by deubiquitinating NLRP3. Rescue studies revealed that NLRP3 overexpression abrogated UCHL5 silencing-mediated biological effects in ox-LDL-treated VSMCs. CONCLUSION UCHL5 modified by METTL14/YTHDF1 axis could facilitate the inflammation and vascular remodeling in atherosclerosis by activating the NLRP3 inflammasome.
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Affiliation(s)
- Xiaohu Yang
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Chen Wang
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Guanglang Zhu
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Zhenyu Guo
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Longhua Fan
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China.
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Zuriaga MA, Fuster JJ. Emerging Role of Acquired Mutations and Clonal Hematopoiesis in Atherosclerosis - Beyond Conventional Cardiovascular Risk Factors. Circ J 2023; 87:394-400. [PMID: 34433749 DOI: 10.1253/circj.cj-21-0505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Accumulating evidence suggests that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, as a substantial risk remains even when these factors are apparently managed well. In this context, clonal hematopoiesis has emerged as a new and potent risk factor for atherosclerotic cardiovascular disease and other cardiometabolic conditions. Clonal hematopoiesis typically arises from somatic mutations that confer a competitive advantage to a mutant hematopoietic stem cell, leading to its clonal expansion in the stem cell population and its progeny of blood leukocytes. Human sequencing studies and experiments in mice suggest that clonal hematopoiesis, at least when driven by certain mutations, contributes to accelerated atherosclerosis development. However, the epidemiology, biology and clinical implications of this phenomenon remain incompletely understood. Here, we review the current understanding of the connection between clonal hematopoiesis and atherosclerosis, and highlight knowledge gaps in this area of research.
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Affiliation(s)
| | - José J Fuster
- Centro Nacional de Investigaciones Cardiovasculares [CNIC].,CIBER en Enfermedades Cardiovasculares [CIBER-CV]
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The mechanism and therapy of aortic aneurysms. Signal Transduct Target Ther 2023; 8:55. [PMID: 36737432 PMCID: PMC9898314 DOI: 10.1038/s41392-023-01325-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 12/15/2022] [Accepted: 01/14/2023] [Indexed: 02/05/2023] Open
Abstract
Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment. To better understand aortic aneurysm, this review elaborates on the discovery history of aortic aneurysm, main classification and clinical manifestations, related molecular mechanisms, clinical cohort studies and animal models, with the ultimate goal of providing insights into the treatment of this devastating disease. The underlying problem with aneurysm disease is weakening of the aortic wall, leading to progressive dilation. If not treated in time, the aortic aneurysm eventually ruptures. An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall. The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.
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Zhou Y, Chai H, Hu Y, Liu R, Jiang H, Fan R, Chen W, Huang F, Chen X. Overexpressed DDX3x promotes abdominal aortic aneurysm formation and activates AKT in ApoE knockout mice. Biochem Biophys Res Commun 2022; 634:138-144. [DOI: 10.1016/j.bbrc.2022.09.077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/02/2022]
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Braunlin E, Abrahante JE, McElmurry R, Evans M, Smith M, Seelig D, O'Sullivan MG, Tolar J, Whitley CB, McIvor RS. Contribution of the innate and adaptive immune systems to aortic dilation in murine mucopolysaccharidosis type I. Mol Genet Metab 2022; 135:193-205. [PMID: 35165009 PMCID: PMC9109621 DOI: 10.1016/j.ymgme.2022.01.104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/23/2021] [Accepted: 01/31/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Adult immunocompetent male C57Bl/6 mucopolysaccharidosis, type I (MPSI) mice develop aortic insufficiency (AI), dilated ascending aortas and decreased cardiac function, findings not observed in immune incompetent adult male NSG MPSI mice. We sought to determine why. METHODS Cardiac ultrasound measurements of ascending aorta and left ventricular dimensions and Doppler interrogation for AI were performed in 6-month-old male B6 MPSI (N = 12), WT (N = 6), NSG MPSI (N = 8), NSG (N = 6) mice. Urinary glycosaminoglycans, RNA sequencing with quantitative PCR were performed and aortic pathology assessed by routine and immunohistochemical staining on subsets of murine aortas. RESULTS Ascending aortic diameters were significantly greater, left ventricular function significantly decreased, and AI significantly more frequent in B6 MPSI mice compared to NSG MPSI mice (p < 0.0001, p = 0.008 and p = 0.02, respectively); NSG and B6 WT mice showed no changes. Urinary glycosaminoglycans were significantly greater in B6 and NSG MPSI mice and both were significantly elevated compared to WT controls (p = 0.003 and p < 0.0001, respectively). By RNA sequencing, all 11 components of the inflammasome pathway were upregulated in B6 MUT, but only Aim2 and Ctsb in NSG MUT mice and none in WT controls. Both B6 and NSG MUT mice demonstrated variably-severe intramural inflammation, vacuolated cells, elastin fragmentation and disarray, and intense glycosaminoglycans on histological staining. B6 MPSI mice demonstrated numerous medial MAC2+ macrophages and adventitial CD3+ T-cells while MAC2+ macrophages were sparse and CD3+ T-cells absent in NSG MPSI mice. CONCLUSIONS Aortic dilation, AI and decreased cardiac function occur in immunocompetent B6 MPSI male mice but not in immune incompetent NSG MPSI mice, unrelated to GAG excretion, upregulation of Ctsb, or routine histologic appearance. Upregulation of all components of the inflammasome pathway in B6 MUT, but not NSG MUT mice, and abundant medial MAC2 and adventitial CD3 infiltrates in B6, but not NSG, MPSI aortas differentiated the two strains. These results suggest that the innate and adaptive immune systems play a role in these cardiac findings which may be relevant to human MPSI.
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Affiliation(s)
- Elizabeth Braunlin
- Department of Pediatrics University of Minnesota Medical School, Minneapolis, MN, USA.
| | - Juan E Abrahante
- University of Minnesota Informatics Institute University of Minnesota, Minneapolis, MN, USA.
| | - Ron McElmurry
- Department of Pediatrics University of Minnesota Medical School, Minneapolis, MN, USA.
| | - Michael Evans
- Biostatistical Design and Analysis Center Clinical and Translational Science Institute University of Minnesota Medical School, Minneapolis, MN, USA.
| | - Miles Smith
- Department of Genetics, Cell Biology and Development University of Minnesota Medical School, Minneapolis, MN, USA.
| | - Davis Seelig
- Comparative Pathology Shared Resource, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, St. Paul, MN, USA.
| | - M Gerard O'Sullivan
- Comparative Pathology Shared Resource, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, St. Paul, MN, USA.
| | - Jakub Tolar
- Department of Blood and Marrow Transplant University of Minnesota Medical School, Minneapolis, MN, USA.
| | - Chester B Whitley
- Gene Therapy Center Department of Pediatrics University of Minnesota Medical School Minneapolis, MN, USA.
| | - R Scott McIvor
- Department of Genetics, Cell Biology and Development University of Minnesota Medical School, Minneapolis, MN, USA.
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Wortmann M, Klotz R, Kalkum E, Dihlmann S, Böckler D, Peters AS. Inflammasome Targeted Therapy as Novel Treatment Option for Aortic Aneurysms and Dissections: A Systematic Review of the Preclinical Evidence. Front Cardiovasc Med 2022; 8:805150. [PMID: 35127865 PMCID: PMC8811141 DOI: 10.3389/fcvm.2021.805150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/28/2021] [Indexed: 12/09/2022] Open
Abstract
Both aortic aneurysm and dissection are life threatening pathologies. In the lack of a conservative medical treatment, the only therapy consists of modifying cardiovascular risk factors and either surgical or endovascular treatment. Like many other cardiovascular diseases, in particular atherosclerosis, aortic aneurysm and dissection have a strong inflammatory phenotype. Inflammasomes are part of the innate immune system. Upon stimulation they form multi protein complexes resulting mainly in activation of interleukin-1β and other cytokines. Considering the gathering evidence, that inflammasomes are decisively involved in the emergence and progression of aortic diseases, inflammasome targeted therapy provides a promising new treatment approach. A systematic review following the PRISMA guidelines on the current preclinical data regarding the potential role of inflammasome targeted drug therapy as novel treatment option for aortic aneurysms and dissections was performed. Included were all rodent models of aortic disease (aortic aneurysm and dissection) evaluating a drug therapy with direct or indirect inhibition of inflammasomes and a suitable control group with the use of the same aortic model without the inflammasome targeted therapy. Primary and secondary outcomes were incidence of aortic disease, aortic rupture, aortic related death, and the maximum aortic diameter. The literature search of MEDLINE (via PubMed), the Web of Science, EMBASE and the Cochrane Central Registry of Registered Trials (CENTRAL) resulted in 8,137 hits. Of these, four studies met the inclusion criteria and were therefore eligible for data analysis. In all of them, targeting of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome effectively reduced the incidence of aortic disease and aortic rupture, and additionally reduced destruction of the aortic wall. Treatment strategies aiming at other inflammasomes could not be identified. In conclusion, inflammasome targeted therapies, more precisely targeting the NLRP3 inflammasome, have shown promising results in rodent models and deserve further investigation in preclinical research to potentially translate them into clinical research for the treatment of human patients with aortic disease. Regarding other inflammasomes, more preclinical research is needed to investigate their role in the pathophysiology of aortic disease. Protocol Registration: PROSPERO 2021 CRD42021279893, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021279893
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Affiliation(s)
- Markus Wortmann
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
- *Correspondence: Markus Wortmann
| | - Rosa Klotz
- Study Center of the German Surgical Society (SDGC), University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Eva Kalkum
- Study Center of the German Surgical Society (SDGC), University of Heidelberg, Heidelberg, Germany
| | - Susanne Dihlmann
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Dittmar Böckler
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Andreas S. Peters
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
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Liu H, Zhang Y, Song W, Sun Y, Jiang Y. Osteopontin N-Terminal Function in an Abdominal Aortic Aneurysm From Apolipoprotein E-Deficient Mice. Front Cell Dev Biol 2021; 9:681790. [PMID: 34458254 PMCID: PMC8397420 DOI: 10.3389/fcell.2021.681790] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 07/20/2021] [Indexed: 12/20/2022] Open
Abstract
The cleavage of osteopontin (OPN) by thrombin results in an N-terminal fragment (OPN-N), which exposes a cryptic integrin-binding motif that promotes the adherence of cells, and plays a proinflammatory role. However, the effect of OPN-N on abdominal aortic aneurysm (AAA) remains unknown. The aim of this study was to investigate the expression of OPN-N in aortic tissue samples obtained from patients, who underwent acute aortic dissection (AD), and normal aorta, effect of OPN-N on angiotensin (Ang) II-induced AAA in mice, and relationship between OPN-N and pyroptosis-related inflammatory factors in vitro. Hematoxylin and eosin staining was conducted to detect histological changes. Next, we detected the expression of the OPN-N protein. Additionally, ApoE−/− mice were divided into four groups: control, control + M5Ab (to block the OPN-N function in mice), Ang II, and Ang II + M5Ab. All mice were euthanized after a 28-day infusion and whole aortas, including thoracic and abdominal aortas, were collected for morphological and histological analysis of the AAA. The OPN-N protein expression was higher in patients with AD than in normal individuals, while histological changes in the aortas of Ang II mice were suppressed in Ang II + M5Ab mice. The expression of OPN-N, NOD-, LRR-, and pyrin domain-containing protein 3, pro-Caspase-1, ASC, Gasdermin-d, interleukin (IL)-18, IL-1β, matrix metalloproteinase (MMP) 2, and MMP9 was lower in the Ang II + M5Ab group than in the Ang II group. The gene expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α was suppressed in the aortic tissues of the Ang II + M5Ab group compared with the Ang II group. Moreover, the expression of α-smooth muscle actin was lower in the Ang II group than in the Ang II + M5Ab group. In vitro results showed that the increase in the expression of pyroptosis-related inflammatory factors induced by OPN was mediated through the nuclear factor (NF)-κB pathway. In conclusion, OPN-N promotes AAA by increasing the expression of pyroptosis-related inflammatory factors through the NF-κB pathway, inflammation, and extracellular matrix degradation. These results highlight the potential of OPN-N as a new therapeutic target to prevent AAA expansion.
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Affiliation(s)
- Hongyang Liu
- Department of Heart Intensive Care Unit, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ying Zhang
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Wei Song
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yancui Sun
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yinong Jiang
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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