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Wang Y, Dou W, Qian X, Chen H, Zhang Y, Yang L, Wu Y, Xu X. Advancements in the study of short-chain fatty acids and their therapeutic effects on atherosclerosis. Life Sci 2025; 369:123528. [PMID: 40049368 DOI: 10.1016/j.lfs.2025.123528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 02/15/2025] [Accepted: 03/02/2025] [Indexed: 03/09/2025]
Abstract
Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.
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Affiliation(s)
- Yongsen Wang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China; Department of Hepatobiliary Pancreatic and Splcnic Surgery, Luzhou People's Hospital, Luzhou, Sichuan 646000, PR China; Department of Vascular and Breast Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan 621000, PR China
| | - Wei Dou
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Xin Qian
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Hao Chen
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Yi Zhang
- Department of Vascular and Breast Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan 621000, PR China
| | - Liu Yang
- Department of Hepatobiliary Pancreatic and Splcnic Surgery, Luzhou People's Hospital, Luzhou, Sichuan 646000, PR China
| | - Ya Wu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Xiongfei Xu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China.
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Wu X, Pan X, Kang J, Huang Y, Ren J, Pan J, Yu K, Li Y. Ferulic acid inhibits ox-LDL-induced ferroptosis and apoptosis in RAW 264.7 cells via the HIF-1 signaling pathway. Front Pharmacol 2025; 16:1524736. [PMID: 40170728 PMCID: PMC11958962 DOI: 10.3389/fphar.2025.1524736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/03/2025] [Indexed: 04/03/2025] Open
Abstract
Objective Ferulic acid (FA) has shown potential in treating atherosclerosis (AS) by improving lipid metabolism and exerting anti-hypoxic effects. This study aimed to validate the mechanism of FA in AS through in vitro experiments. Methods Network analysis was employed to predict the mechanisms underlying the therapeutic effects of FA on AS. An in vitro foam cell model was established using RAW 264.7 cells treated with ox-LDL. Cellular lipid accumulation was detected using Oil Red O staining; cell viability was assessed by cell counting kit-8; mitochondrial morphology and function were evaluated by transmission electron microscopy and JC-1 staining; apoptosis levels were detected by TUNEL and DAPI staining; mitochondrial Fe2+ content was measured by Mito-FerroGreen; and Western blot was performed to determine the protein expression levels of HIF-1α, Bax, Bcl2, GPX4, and EGFR. Results Network analysis suggested that FA may exert its therapeutic effects on AS through the HIF-1 signaling pathway and is closely associated with the regulation of ferroptosis and apoptosis. FA upregulated the expression of ALOX5, BCL2, ERN1, GPX4, NOS3, and SLC2A1 mRNA and downregulated the expression of BAX, CYCS, EGFR, FLT1, HIF1A, NFKB1, NOS2, PARP1, and STAT3 mRNA. In vitro experiments demonstrated that FA reduces lipid accumulation, increases cell viability, improves mitochondrial function, and decreases reactive oxygen species content. Additionally, FA inhibited ferroptosis and apoptosis by suppressing the HIF-1 signaling pathway, up-regulating the expression of GPX4 and Bcl2, and down-regulating the expression of HIF-1α and Bax protein. HIF-1 agonists reversed these effects by activating the HIF-1 signaling pathway. Conclusion FA improves mitochondrial function and suppresses ferroptosis and apoptosis by inhibiting the HIF-1 signaling pathway, thereby treating AS.
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Affiliation(s)
- Xize Wu
- The First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Xue Pan
- College of Traditional Chinese Medicine, Dazhou Vocational College of Chinese Medicine, Dazhou, Sichuan, China
| | - Jian Kang
- The First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Yuxi Huang
- The First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Jiaqi Ren
- The First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Jiaxiang Pan
- Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Kaifeng Yu
- Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Yue Li
- Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
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3
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Zhang H, Sáenz de Urturi D, Fernández-Tussy P, Huang Y, Jovin DG, Zhang X, Huang S, Lek M, da Silva Catarino J, Sternak M, Citrin KM, Swirski FK, Gustafsson JÅ, Greif DM, Esplugues E, Biwer LA, Suárez Y, Fernández-Hernando C. Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function. Proc Natl Acad Sci U S A 2025; 122:e2417512122. [PMID: 40035761 PMCID: PMC11912459 DOI: 10.1073/pnas.2417512122] [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: 08/29/2024] [Accepted: 01/23/2025] [Indexed: 03/06/2025] Open
Abstract
Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery's media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1, Srebf1, Scd1, Scd2, Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.
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MESH Headings
- Liver X Receptors/metabolism
- Liver X Receptors/genetics
- Animals
- Mice
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Signal Transduction
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Hypercholesterolemia/metabolism
- Hypercholesterolemia/pathology
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/pathology
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Vascular Remodeling
- Humans
- Mice, Knockout
- Male
- Mice, Inbred C57BL
- Lipid Metabolism
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Affiliation(s)
- Hanming Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Diego Sáenz de Urturi
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Pablo Fernández-Tussy
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Yan Huang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Daniel G. Jovin
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT06511
| | - Xinbo Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Shushu Huang
- Deparment of Genetics, Yale University School of Medicine, New Haven, CT06510
| | - Monkol Lek
- Deparment of Genetics, Yale University School of Medicine, New Haven, CT06510
| | | | - Magdalena Sternak
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Kathryn M. Citrin
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
- Department of Cellular & Molecular Physiology, Yale University, New Haven, CT06510
| | - Fillip K. Swirski
- Caridovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY10029
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY10029
| | - Jan-Åke Gustafsson
- Department of Biology and Biochemistry, Center of Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX77204
| | - Daniel M. Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT06511
- Deparment of Genetics, Yale University School of Medicine, New Haven, CT06510
| | - Enric Esplugues
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Lauren A. Biwer
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
- Department of Pathology, Yale University School of Medicine, New Haven, CT06520
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT06520
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT06520
- Department of Pathology, Yale University School of Medicine, New Haven, CT06520
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Lambert J, Jørgensen HF. Epigenetic regulation of vascular smooth muscle cell phenotypes in atherosclerosis. Atherosclerosis 2025; 401:119085. [PMID: 39709233 DOI: 10.1016/j.atherosclerosis.2024.119085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 12/23/2024]
Abstract
Vascular smooth muscle cells (VSMCs) in adult arteries maintain substantial phenotypic plasticity, which allows for the reversible cell state changes that enable vascular remodelling and homeostasis. In atherosclerosis, VSMCs dedifferentiate in response to lipid accumulation and inflammation, resulting in loss of their characteristic contractile state. Recent studies showed that individual, pre-existing VSMCs expand clonally and can acquire many different phenotypes in atherosclerotic lesions. The changes in gene expression underlying this phenotypic diversity are mediated by epigenetic modifications which affect transcription factor access and thereby gene expression dynamics. Additionally, epigenetic mechanisms can maintain cellular memory, potentially facilitating reversion to the contractile state. While technological advances have provided some insight, a comprehensive understanding of how VSMC phenotypes are governed in disease remains elusive. Here we review current literature in light of novel insight from studies at single-cell resolution. We also discuss how lessons from epigenetic studies of cellular regulation in other fields could help in translating the potential of targeting VSMC phenotype conversion into novel therapies in cardiovascular disease.
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Affiliation(s)
- Jordi Lambert
- Section of Cardiorespiratory Medicine, University of Cambridge, VPD Heart and Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge, CB2 0BB, UK.
| | - Helle F Jørgensen
- Section of Cardiorespiratory Medicine, University of Cambridge, VPD Heart and Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge, CB2 0BB, UK.
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5
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Liang X, Tian S, Zhang H, Sun S, Zhang P, Li J, Li Y, Zhang Y, Liu Z. Efferocytosis: A new star of atherosclerotic plaques reversal. Int Immunopharmacol 2025; 146:113904. [PMID: 39724733 DOI: 10.1016/j.intimp.2024.113904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 12/16/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
Efferocytosis is considered the key to eliminate apoptotic cells (ACs) under physiological and pathological conditions in vivo, mainly through different types of macrophages to achieve this process. Especially, tissue-resident macrophages (TRMs) are very significant for inflammation regression and maintenance of homeostasis in vivo. Abnormal efferocytosis will lead to the accumulation of ACs and the release of a variety of pro-inflammatory factors, which mediates the occurrence of many inflammatory diseases, including atherosclerosis (AS). AS is a chronic inflammatory vascular disease with the participation of the immune system. Defective efferocytosis will accelerate the progress of AS to a certain extent. Therefore, it is of great significance to understand the mechanism of efferocytosis and realize the prevention and treatment of AS through efferocytosis. In this review, we will briefly describe the specific process of efferocytosis, deeply discuss the possible molecular mechanism of impaired efferocytosis promoting the development of AS, and summarize the ways to prevent and treat AS through efferocytosis intervention therapy.
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Affiliation(s)
- Xiangyu Liang
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Shuoqi Tian
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Han Zhang
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Shusen Sun
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Peixiang Zhang
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Jiameng Li
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Yong Li
- Beijing Yongkang Nian Health Technology Co., Ltd., Beijing, China.
| | - Yanfen Zhang
- Technology Transfer Center, Hebei University, Baoding, China.
| | - Zhongcheng Liu
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
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6
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Cheng WH, Wang Y. Inflammatory Pathways in Coronary Artery Disease: Which Ones to Target for Secondary Prevention? Cells 2025; 14:153. [PMID: 39936945 PMCID: PMC11817712 DOI: 10.3390/cells14030153] [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: 01/02/2025] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 02/13/2025] Open
Abstract
Coronary artery disease (CAD), the build-up of atherosclerotic plaques on the wall of blood vessels, causes adverse cardiovascular events. Secondary prevention focuses on treating patients with existing plaques to prevent disease progression. Recent studies have shown that inflammation is an independent risk factor that drives disease progression, and targeting inflammation could be an effective therapeutic strategy for secondary prevention. In this review, we highlighted the roles of several inflammatory pathways in rupture and erosion, two major processes through which established plaques lead to adverse cardiovascular events. In the past 15 years, numerous clinical trials have tested the therapeutic potential of targeting these pathways, including neutralizing inflammatory cytokines and blocking signaling transduction of the inflammatory pathways. Only colchicine was approved for clinical use in patients with CAD. This is primarily due to the multifaceted roles of inflammatory pathways in disease progression. Commonly used pre-clinical models provided robust information for the onset of early disease but limited understanding of the inflammatory network in established plaques. This review will summarize lessons learned from successful and failed clinical trials to advocate for assessing inflammation in established plaques before designing therapeutics for secondary prevention.
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Affiliation(s)
- Wan-Hei Cheng
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada;
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada;
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
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7
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Liang Y, Dong L, Yan J, Yang Y, Liu Y, Wu H, Shi X, Dai M. Paeonol attenuates atherosclerosis by regulating vascular smooth muscle cells apoptosis and modulating immune cells infiltration through reducing LTβR expression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156196. [PMID: 39520955 DOI: 10.1016/j.phymed.2024.156196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/26/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory disease with multicellular participation, and the decrease of plaque stability induces the occurrence of clinical adverse events. In order to update the clinical treatment strategy of atherosclerosis, it is necessary to clarify the mechanism of plaque stabilization, especially to explore the targets of vascular smooth muscle cells (VSMCs) apoptosis and immune cell infiltration. Paeonol (Pae), a major phenolic compound derived from the bark of Paeonia albiflora Andr., has been proved to have anti-inflammatory properties in atherosclerosis. However, the pharmacological mechanisms of Pae in improving atherosclerosis remain unclear, particularly with regard to the role of stabilizing vulnerable plaques. PURPOSE This study is aiming to elucidate the effect of Pae against atherosclerotic unstable plaque, and to further explore the potential mechanism of Pae in inhibiting VSMCs apoptosis and immune cell infiltration. METHODS A high-fat diet (HFD) induced atherosclerosis mice model was established in ApoE-/- mice, Pae in two different dosages and simvastatin (SIM) were than administrated for another 4 weeks. Atherosclerotic plaque formation and lipid accumulation were assessed with hematoxylin and eosin (H&E) staining and oil red O staining. Immunofluorescence were employed to examine the general condition of mice and the protective effect of Pae on plaque progression. Cell apoptosis was assessed via TUNNEL staining and flow cytometry. The mRNA and protein expressions in aorta tissue was detected by RT-PCR and western blotting. To investigate the effect of Pae on the regulation of the LTβR/NIK/caspase-3 pathway, VSMCs were extracted from the aorta of C57BL/6 J mice and treated with LTα1β2. RESULTS Here, we show that Pae significantly inhibited atherosclerosis progression and stabilized vulnerable plaques in ApoE-/- mice, in association with decreased T/B cell infiltration and VSMC apoptosis. Notably, the number of plaque-infiltrating T/B cells showed a linear positive correlation with apoptotic VSMCs, and VSMCs sensitive to apoptosis expressed LTβR, which might be activated by LTα1β2-expressing T/B cells. Moreover, the protein expression of LTβR in VSMCs was decreased in plaques after treatment of Pae. Mechanistically, Pae treatment inhibited LTα1β2 stimulated VSMCs apoptosis via LTβR/NIK/caspase-3 signaling pathway in vitro. Importantly, LTβR overexpression increased the VSMCs apoptosis and plaque instability in ApoE-/- mice, partially reversing the protective effect of Pae. CONCLUSION Inhibition of LTβR signaling represents a promising strategy that exerts therapeutic effects through the combined suppression of immune cell infiltration and VSMCs apoptosis, providing novel insights into the anti-atherosclerosis mechanisms of Pae.
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Affiliation(s)
- Yuning Liang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Lishun Dong
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Jinjin Yan
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yulong Yang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yarong Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China
| | - Hongfei Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China
| | - Xiaoyan Shi
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China.
| | - Min Dai
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China.
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8
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Richardson KC, Jung K, Matsubara JA, Choy JC, Granville DJ. Granzyme B in aging and age-related pathologies. Trends Mol Med 2024; 30:1165-1179. [PMID: 39181801 DOI: 10.1016/j.molmed.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024]
Abstract
Aging is a major risk factor for pathologies that manifest later in life. Much attention is devoted towards elucidating how prolonged environmental exposures and inflammation promote biological (accelerated) tissue aging. Granzymes, a family of serine proteases, are increasingly recognized for their emerging roles in biological aging and disease. Widely recognized as intracellular mediators of cell death, granzymes, particularly granzyme B (GzmB), also accumulate in the extracellular milieu of tissues with age, contributing to chronic tissue injury, inflammation, and impaired healing. Consequently, this has prompted the field to reconsider how GzmB regulation, accumulation, and proteolysis impact health and disease with age. While GzmB is observed in numerous age-related conditions, the current review focuses on mechanistic studies where proof-of-concept has been forwarded.
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Affiliation(s)
- Katlyn C Richardson
- International Collaboration On Repair Discoveries (ICORD) Centre, Department of Pathology and Laboratory Medicine, British Columbia Professional Firefighters' Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Karen Jung
- International Collaboration On Repair Discoveries (ICORD) Centre, Department of Pathology and Laboratory Medicine, British Columbia Professional Firefighters' Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Joanne A Matsubara
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - David J Granville
- International Collaboration On Repair Discoveries (ICORD) Centre, Department of Pathology and Laboratory Medicine, British Columbia Professional Firefighters' Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada; Centre for Heart Lung Innovation, Providence Research, University of British Columbia, Vancouver, BC, Canada.
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9
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Yin Z, Zhang J, Shen Z, Qin J, Wan J, Wang M. Regulated vascular smooth muscle cell death in vascular diseases. Cell Prolif 2024; 57:e13688. [PMID: 38873710 PMCID: PMC11533065 DOI: 10.1111/cpr.13688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/13/2024] [Accepted: 05/27/2024] [Indexed: 06/15/2024] Open
Abstract
Regulated cell death (RCD) is a complex process that involves several cell types and plays a crucial role in vascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant elements of the medial layer of blood vessels, and their regulated death contributes to the pathogenesis of vascular diseases. The types of regulated VSMC death include apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy-dependent cell death (ADCD). In this review, we summarize the current evidence of regulated VSMC death pathways in major vascular diseases, such as atherosclerosis, vascular calcification, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, neointimal hyperplasia, and inherited vascular diseases. All forms of RCD constitute a single, coordinated cell death system in which one pathway can compensate for another during disease progression. Pharmacologically targeting RCD pathways has potential for slowing and reversing disease progression, but challenges remain. A better understanding of the role of regulated VSMC death in vascular diseases and the underlying mechanisms may lead to novel pharmacological developments and help clinicians address the residual cardiovascular risk in patients with cardiovascular diseases.
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Affiliation(s)
- Zheng Yin
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of GeriatricsZhongnan Hospital of Wuhan University, Wuhan UniversityWuhanChina
- Cardiovascular Research Institute, Wuhan UniversityWuhanChina
- Hubei Key Laboratory of CardiologyWuhanChina
| | - Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of GeriatricsZhongnan Hospital of Wuhan University, Wuhan UniversityWuhanChina
- Cardiovascular Research Institute, Wuhan UniversityWuhanChina
- Hubei Key Laboratory of CardiologyWuhanChina
| | - Zican Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of GeriatricsZhongnan Hospital of Wuhan University, Wuhan UniversityWuhanChina
- Cardiovascular Research Institute, Wuhan UniversityWuhanChina
- Hubei Key Laboratory of CardiologyWuhanChina
| | - Juan‐Juan Qin
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of GeriatricsZhongnan Hospital of Wuhan University, Wuhan UniversityWuhanChina
- Center for Healthy Aging, Wuhan University School of NursingWuhanChina
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of GeriatricsZhongnan Hospital of Wuhan University, Wuhan UniversityWuhanChina
- Cardiovascular Research Institute, Wuhan UniversityWuhanChina
- Hubei Key Laboratory of CardiologyWuhanChina
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of GeriatricsZhongnan Hospital of Wuhan University, Wuhan UniversityWuhanChina
- Cardiovascular Research Institute, Wuhan UniversityWuhanChina
- Hubei Key Laboratory of CardiologyWuhanChina
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10
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Guo J, Du L. An update on ox-LDL-inducing vascular smooth muscle cell-derived foam cells in atherosclerosis. Front Cell Dev Biol 2024; 12:1481505. [PMID: 39524227 PMCID: PMC11543427 DOI: 10.3389/fcell.2024.1481505] [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: 08/16/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
Excess cholesterol accumulation induces the accumulation of foam cells, eventually accelerating atherosclerosis progress. Historically, the mechanisms of macrophage-derived foam cells have attracted attention because of their central role in plaque development, which was challenged by lineage tracing in union with single-cell sequencing (sc-seq). Accumulated studies have uncovered how vascular smooth muscle cells (VSMCs) proliferate and migrate to the vascular intima and accumulate, then transform into foam cells induced by surplus lipids, finally accounting for 30% to 70% of the total foam cells within the plaque of both mice and humans. Therefore, the mechanisms of VSMC-derived foam cells have received increasing attention. The review intends to summarize the transformation mechanism of VSMCs into foam cells induced by oxidized low-density lipoproteins (ox-LDL) in atherosclerosis.
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Affiliation(s)
- Jingjing Guo
- Luoyang Key Laboratory of Cardiovascular Science, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Laijing Du
- Department of Cardiology, Henan Key Laboratory of Cardiovascular Science, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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11
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Kim DH. Endoplasmic reticulum stress induces hepatic steatosis through interaction between PPARα and FoxO6 in vivo and in vitro. J Mol Med (Berl) 2024; 102:1267-1284. [PMID: 39198274 PMCID: PMC11416408 DOI: 10.1007/s00109-024-02480-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024]
Abstract
Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress-induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress-induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study-lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. KEY MESSAGES: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice.
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Affiliation(s)
- Dae Hyun Kim
- Department of Food Science & Technology, College of Natural Resources and Life Science, Pusan National University, Miryang-Si, Gyeongsangnam-Do, 50463, Republic of Korea.
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12
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Chen Y, Gialeli C, Shen J, Dunér P, Walse B, Duelli A, Caing-Carlsson R, Blom AM, Zibert JR, Nilsson AH, Alenfall J, Liang C, Nilsson J. Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis. Pharmacol Res 2024; 205:107259. [PMID: 38871237 DOI: 10.1016/j.phrs.2024.107259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/10/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024]
Abstract
The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.
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Affiliation(s)
- Yihong Chen
- Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai Cardiovascular Institute of Integrative Medicine, Shanghai, China; Department of Experimental Medical Science, Lund University, Sweden
| | | | - Junyan Shen
- Department of Experimental Medical Science, Lund University, Sweden; Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Pontus Dunér
- Department of Clinical Sciences Malmö, Lund University, Sweden
| | | | | | | | - Anna M Blom
- Department of Translational Medicine, Lund University, Sweden
| | | | | | - Jan Alenfall
- Department of Clinical Sciences Malmö, Lund University, Sweden; Coegin Pharma AB, Lund, Sweden
| | - Chun Liang
- Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai Cardiovascular Institute of Integrative Medicine, Shanghai, China.
| | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, Sweden.
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13
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Wang X, Liu L, Zhai L, Palade P, Wang X, Mehta JL. Direct Impact of PCSK9 on SMC Senescence and Apoptosis: A New Focus in Cardiovascular Diseases. Arterioscler Thromb Vasc Biol 2024; 44:1491-1496. [PMID: 38924434 DOI: 10.1161/atvbaha.124.320140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024]
Affiliation(s)
- Xiaoping Wang
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China (Xiaoping Wang, L.L., L.Z., Xianwei Wang)
- Department of Human Anatomy and Histoembryology (Xiaoping Wang, L.L., Xianwei Wang), Xinxiang Medical University, China
| | - Lu Liu
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China (Xiaoping Wang, L.L., L.Z., Xianwei Wang)
- Department of Human Anatomy and Histoembryology (Xiaoping Wang, L.L., Xianwei Wang), Xinxiang Medical University, China
| | - Liyue Zhai
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China (Xiaoping Wang, L.L., L.Z., Xianwei Wang)
- Henan Key Laboratory of Medical Tissue Regeneration (L.Z., Xianwei Wang), Xinxiang Medical University, China
| | - Philip Palade
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock (P.P.)
| | - Xianwei Wang
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China (Xiaoping Wang, L.L., L.Z., Xianwei Wang)
- Department of Human Anatomy and Histoembryology (Xiaoping Wang, L.L., Xianwei Wang), Xinxiang Medical University, China
- Henan Key Laboratory of Medical Tissue Regeneration (L.Z., Xianwei Wang), Xinxiang Medical University, China
| | - Jawahar L Mehta
- Department of Medicine (Cardiology), University of Arkansas for Medical Sciences and the Veterans Affairs Medical Center, Little Rock (J.L.M.)
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14
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Sun Y, Li F, Zhou Y, Liu A, Lin X, Zou Z, Lv X, Zhou J, Li Z, Wu X, Dou S, Zhang M, Zhu J, Chen Y, Xiao X, Hu Y, Li H, Li Y. Nonlinear association between atherogenic index of plasma and type 2 diabetes mellitus in overweight and obesity patients: evidence from Chinese medical examination data. Cardiovasc Diabetol 2024; 23:226. [PMID: 38951808 PMCID: PMC11218131 DOI: 10.1186/s12933-024-02330-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 06/19/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND The atherogenic index of plasma (AIP) is closely associated with the onset of diabetes, with obesity being a significant risk factor for type 2 diabetes mellitus (T2DM). However, the association between the AIP and T2DM in overweight and obese populations has been infrequently studied. Therefore, this study aimed to explore this association in overweight and obese individuals with T2DM. METHODS This cross-sectional analysis utilized data from 40,633 participants with a body mass index (BMI) ≥ 24 kg/m2 who were screened from January 2018 to December 2023 at Henan Provincial People's Hospital. Participants were categorized into groups of overweight and obese individuals with and without diabetes according to the T2DM criteria. The AIP, our dependent variable, was calculated using the formula log10 [(TG mol/L)/HDL-C (mol/L)]. We investigated the association between the AIP and T2DM in overweight and obese individuals using multivariate logistic regression, subgroup analysis, generalized additive models, smoothed curve fitting, and threshold effect analysis. Additionally, mediation analysis evaluated the role of inflammatory cells in AIP-related T2DM. RESULTS Overweight and obese patients with T2DM exhibited higher AIP levels than those without diabetes. After adjusting for confounders, our results indicated a significant association between the AIP and the risk of T2DM in overweight and obese individuals (odds ratio (OR) = 5.17, 95% confidence interval (CI) 4.69-5.69). Notably, participants with a high baseline AIP (Q4 group) had a significantly greater risk of T2DM than those in the Q1 group, with an OR of 3.18 (95% CI 2.94-3.45). Subgroup analysis revealed that the association between the AIP and T2DM decreased with increasing age (interaction P < 0.001). In overweight and obese populations, the association between AIP and T2DM risk displayed a J-shaped nonlinear pattern, with AIP > - 0.07 indicating a significant increase in T2DM risk. Various inflammatory cells, including neutrophils, leukocytes, and monocytes, mediated 4.66%, 4.16%, and 1.93% of the associations, respectively. CONCLUSION In overweight and obese individuals, the AIP was independently associated with T2DM, exhibiting a nonlinear association. Additionally, the association between the AIP and T2DM decreased with advancing age. Multiple types of inflammatory cells mediate this association.
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Affiliation(s)
- Yongbing Sun
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Fengli Li
- Department of Bariatric Metabolic Surgery, Central Hospital of Zhengzhou University, #195 Tongbai Road, Zhengzhou, 450003, Henan, China
| | - Yang Zhou
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Ao Liu
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Xinbei Lin
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Zhi Zou
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Xue Lv
- Henan Provincial People's Hospital, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Jing Zhou
- Henan Provincial Research Center of Clinical Medicine of Nephropathy, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, #7 Wei Wu Road, Zhengzhou, 450003, China
| | - Zhonglin Li
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Xiaoling Wu
- Department of Nuclear Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
| | - Shewei Dou
- Department of Medical Imaging, People's Hospital of Zhengzhou University, #7 Wei Wu Road, Zhengzhou, 450003, Henan, China
| | - Michael Zhang
- Sevenoaks Health Management Center, Canada-Canada Institute of Health Engineering, University of Manitoba, Winnipeg, Canada
| | - Jiadong Zhu
- Chronic Health Management Laboratory, Department of Health Management, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yalong Chen
- Department of Medical Imaging, Central Hospital of Zhengzhou University, #195 Tongbai Road, Zhengzhou, 450003, Henan, China
| | - Xinguang Xiao
- Department of Medical Imaging, Central Hospital of Zhengzhou University, #195 Tongbai Road, Zhengzhou, 450003, Henan, China
| | - Yangxi Hu
- Department of Bariatric Metabolic Surgery, Central Hospital of Zhengzhou University, #195 Tongbai Road, Zhengzhou, 450003, Henan, China.
| | - Hao Li
- Fuwaihua Central Vascular Disease Hospital, #1 Fuwai Avenue, Zhengzhou, 451464, Henan, China.
| | - Yongli Li
- Chronic Health Management Laboratory, Department of Health Management, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
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15
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Stroope C, Nettersheim FS, Coon B, Finney AC, Schwartz MA, Ley K, Rom O, Yurdagul A. Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities. Nat Metab 2024; 6:617-638. [PMID: 38532071 PMCID: PMC11055680 DOI: 10.1038/s42255-024-01015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 02/20/2024] [Indexed: 03/28/2024]
Abstract
Accumulating evidence over the past decades has revealed an intricate relationship between dysregulation of cellular metabolism and the progression of atherosclerotic cardiovascular disease. However, an integrated understanding of dysregulated cellular metabolism in atherosclerotic cardiovascular disease and its potential value as a therapeutic target is missing. In this Review, we (1) summarize recent advances concerning the role of metabolic dysregulation during atherosclerosis progression in lesional cells, including endothelial cells, vascular smooth muscle cells, macrophages and T cells; (2) explore the complexity of metabolic cross-talk between these lesional cells; (3) highlight emerging technologies that promise to illuminate unknown aspects of metabolism in atherosclerosis; and (4) suggest strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas with a potential new generation of cardiovascular therapeutics.
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Affiliation(s)
- Chad Stroope
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Felix Sebastian Nettersheim
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Department of Cardiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Brian Coon
- Yale Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Cardiovascular Biology Research Program, OMRF, Oklahoma City, OK, USA
- Department of Cell Biology, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA
| | - Alexandra C Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Martin A Schwartz
- Yale Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Klaus Ley
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, San Diego, CA, USA
- Immunology Center of Georgia (IMMCG), Augusta University Immunology Center of Georgia, Augusta, GA, USA
| | - Oren Rom
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Arif Yurdagul
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
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16
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Zhou G, Liu Y, Wu H, Zhang D, Yang Q, Li Y. Research Progress on Histone Deacetylases Regulating Programmed Cell Death in Atherosclerosis. J Cardiovasc Transl Res 2024; 17:308-321. [PMID: 37821683 DOI: 10.1007/s12265-023-10444-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 09/28/2023] [Indexed: 10/13/2023]
Abstract
Histone deacetylases (HDACs) are epigenetic modifying enzyme that is closely related to chromatin structure and gene transcription, and numerous studies have found that HDACs play an important regulatory role in atherosclerosis disease. Apoptosis, autophagy and programmed necrosis as the three typical programmed cell death modalities that can lead to cell loss and are closely related to the developmental process of atherosclerosis. In recent years, accumulating evidence has shown that the programmed cell death mediated by HDACs is increasingly important in the pathophysiology of atherosclerosis. This paper first gives a brief overview of HDACs, the mechanism of programmed cell death, and their role in atherosclerosis, and then further elaborates on the role and mechanism of HDACs in regulating apoptosis, autophagy, and programmed necrosis in atherosclerosis, respectively, to provide new effective measures and theoretical basis for the prevention and treatment of atherosclerosis.
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Affiliation(s)
- Gang Zhou
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Yanfang Liu
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Hui Wu
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China.
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China.
- Department of Cardiology, Yichang Central People's Hospital, Yiling Road 183, Yichang, 443003, Hubei, China.
| | - Dong Zhang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Qingzhuo Yang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Yi Li
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
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17
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Gwon JG, Lee SM. Role of PTEN-Induced Protein Kinase 1 as a Mitochondrial Dysfunction Regulator in Cardiovascular Disease Pathogenesis. Vasc Specialist Int 2024; 40:9. [PMID: 38486493 PMCID: PMC10940882 DOI: 10.5758/vsi.230116] [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: 11/21/2023] [Revised: 01/29/2024] [Accepted: 02/07/2024] [Indexed: 03/17/2024] Open
Abstract
Cardiovascular disease (CVD) remains a global health challenge, primarily due to atherosclerosis, which leads to conditions such as coronary artery disease, cerebrovascular disease, and peripheral arterial disease. Mitochondrial dysfunction initiates endothelial dysfunction, a key contributor to CVD pathogenesis, as well as triggers the accumulation of reactive oxygen species (ROS), energy stress, and cell death in endothelial cells, which are crucial for atherosclerosis development. This review explores the role of PTEN-induced protein kinase 1 (PINK1) in mitochondrial quality control, focusing on its significance in cardiovascular health. PINK1 plays a pivotal role in mitophagy (selective removal of damaged mitochondria), contributing to the prevention of CVD progression. PINK1-mediated mitophagy also affects the maintenance of cardiomyocyte homeostasis in ischemic heart disease, thus mitigating mitochondrial dysfunction and oxidative stress, as well as regulates endothelial health in atherosclerosis through influencing ROS levels and inflammatory response. We also investigated the role of PINK1 in vascular smooth muscle cells, emphasizing on its role in apoptosis and atherosclerosis. Dysfunctional mitophagy in these cells accelerates cellular senescence and contributes to adverse effects including plaque rupture and inflammation. Mitophagy has also been explored as a potential therapeutic target for vascular calcification, a representative lesion in atherosclerosis, with a focus on lactate-induced mechanisms. Finally, we highlight the current research and clinical trials targeting mitophagy as a therapeutic avenue for CVD.
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Affiliation(s)
- Jun Gyo Gwon
- Division of Vascular Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung Min Lee
- Department of Convergence Medicine and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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18
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Long F, Zhou X, Zhang J, Di C, Li X, Ye H, Pan J, Si J. The role of lncRNA HCG18 in human diseases. Cell Biochem Funct 2024; 42:e3961. [PMID: 38425124 DOI: 10.1002/cbf.3961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/29/2024] [Accepted: 02/16/2024] [Indexed: 03/02/2024]
Abstract
A substantial number of long noncoding RNAs (lncRNAs) have been identified as potent regulators of human disease. Human leukocyte antigen complex group 18 (HCG18) is a new type of lncRNA that has recently been proven to play an important role in the occurrence and development of various diseases. Studies have found that abnormal expression of HCG18 is closely related to the clinicopathological characteristics of many diseases. More importantly, HCG18 was also found to promote disease progression by affecting a series of cell biological processes. This article mainly discusses the expression characteristics, clinical characteristics, biological effects and related regulatory mechanisms of HCG18 in different human diseases, providing a scientific theoretical basis for its early clinical application.
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Affiliation(s)
- Feng Long
- Key Laboratory of TCM Prevention and Treatment of Chronic Diseases, School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xuan Zhou
- Key Laboratory of TCM Prevention and Treatment of Chronic Diseases, School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jinhua Zhang
- Department of Medical Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Cuixia Di
- Department of Medical Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Xue Li
- Key Laboratory of TCM Prevention and Treatment of Chronic Diseases, School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Hailin Ye
- Key Laboratory of TCM Prevention and Treatment of Chronic Diseases, School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jingyu Pan
- Key Laboratory of TCM Prevention and Treatment of Chronic Diseases, School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jing Si
- Department of Medical Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
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19
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Bagheri B, Khatibiyan Feyzabadi Z, Nouri A, Azadfallah A, Mahdizade Ari M, Hemmati M, Darban M, Alavi Toosi P, Banihashemian SZ. Atherosclerosis and Toll-Like Receptor4 (TLR4), Lectin-Like Oxidized Low-Density Lipoprotein-1 (LOX-1), and Proprotein Convertase Subtilisin/Kexin Type9 (PCSK9). Mediators Inflamm 2024; 2024:5830491. [PMID: 38445291 PMCID: PMC10914434 DOI: 10.1155/2024/5830491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 01/31/2024] [Accepted: 02/16/2024] [Indexed: 03/07/2024] Open
Abstract
Atherosclerosis is a leading cause of death in the world. A significant body of evidence suggests that inflammation and various players are implicated and have pivotal roles in the formation of atherosclerotic plaques. Toll-like receptor 4 (TLR4) is linked with different stages of atherosclerosis. This receptor is highly expressed in the endothelial cells (ECs) and atherosclerotic plaques. TLR4 activation can lead to the production of inflammatory cytokines and related responses. Lectin-like oxidized low-density lipoprotein-1 (LOX-1), an integral membrane glycoprotein with widespread expression on the ECs, is involved in atherosclerosis and has some common pathways with TLR4 in atherosclerotic lesions. In addition, proprotein convertase subtilisin/kexin type9 (PCSK9), which is a regulatory enzyme with different roles in cholesterol uptake, is implicated in atherosclerosis. At present, TLR4, PCSK9, and LOX-1 are increasingly acknowledged as key players in the pathogenesis of atherosclerotic cardiovascular diseases. Herein, we presented the current evidence on the structure, functions, and roles of TLR4, PCSK9, and LOX-1 in atherosclerosis.
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Affiliation(s)
- Bahador Bagheri
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | | | - Ahmad Nouri
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Azadfallah
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahyar Mahdizade Ari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Maral Hemmati
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahboubeh Darban
- Department of Internal Medicine, Kowsar Hospital, Semnan University of Medical Sciences, Semnan, Iran
| | - Parisa Alavi Toosi
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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Ahmad P, Siqueira WL. Polymorphism of salivary proteins and risk of periodontal diseases: A systematic review and meta-analysis of clinical studies. J Dent 2024; 141:104804. [PMID: 38122885 DOI: 10.1016/j.jdent.2023.104804] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/17/2023] [Accepted: 12/10/2023] [Indexed: 12/23/2023] Open
Abstract
OBJECTIVES The present systematic review and meta-analysis aimed to assess the association between salivary protein polymorphisms and the risk of periodontal diseases (PD). DATA The review incorporated cross-sectional, case-control, retrospective/prospective cohort, and randomized controlled trials assessing the influence of salivary protein polymorphisms on the risk of PD development were included in this review. SOURCES A thorough literature search was conducted across electronic databases, namely PubMed, Scopus, Embase, and Web of Science, without any restrictions on publication language and year. STUDY SELECTION A total of 168 studies were identified, of which 19 were eligible for inclusion. The risk of bias (RoB) assessment of the included studies was conducted at the methodological level. RESULTS A total of 16 studies were included. Polymorphism in the gene encoding TNF-α was found to be protective against gingivitis, while those encoding IL-1α and IL-1β were associated with developing gingivitis. Of the 42 proteins investigated, various gene polymorphisms were identified as protective or risk factors for periodontitis. Protective genes include CFH, DNMT1, OPRM1, and TLR9. Conversely, certain salivary protein genes (e.g., CRP, ERN1, FAM5C, IDH2, LTA, TET2, MPA, NLRP3, TLR4) were associated with periodontitis risk. Notably, IL6, MMP9, and MUC7 genes showed no association with PD, while MMP13 was linked to early implant loss. Overall, the meta-analysis found a statistically significant association between salivary proteins' polymorphisms and risk of PD. CONCLUSIONS Salivary protein polymorphisms significantly influence PD, revealing protective and risk-associated genotypes. Despite limitations, findings suggest therapeutic targets, emphasizing the complex genetics-periodontal health interplay. CLINICAL SIGNIFICANCE This study unveils salivary protein polymorphisms as pivotal factors in PD. Protective genes including CFH and TLR9, and risk-associated genes including CRP and TLR4, indicate a genetic basis for PD susceptibility.
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Affiliation(s)
- Paras Ahmad
- College of Dentistry, University of Saskatchewan, Saskatoon, S7N E5E, Saskatchewan, Canada
| | - Walter Luiz Siqueira
- College of Dentistry, University of Saskatchewan, Saskatoon, S7N E5E, Saskatchewan, Canada.
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21
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He J, Gao Y, Yang C, Guo Y, Liu L, Lu S, He H. Navigating the landscape: Prospects and hurdles in targeting vascular smooth muscle cells for atherosclerosis diagnosis and therapy. J Control Release 2024; 366:261-281. [PMID: 38161032 DOI: 10.1016/j.jconrel.2023.12.047] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/02/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024]
Abstract
Vascular smooth muscle cells (VSMCs) have emerged as pivotal contributors throughout all phases of atherosclerotic plaque development, effectively dispelling prior underestimations of their prevalence and significance. Recent lineage tracing studies have unveiled the clonal nature and remarkable adaptability inherent to VSMCs, thereby illuminating their intricate and multifaceted roles in the context of atherosclerosis. This comprehensive review provides an in-depth exploration of the intricate mechanisms and distinctive characteristics that define VSMCs across various physiological processes, firmly underscoring their paramount importance in shaping the course of atherosclerosis. Furthermore, this review offers a thorough examination of the significant strides made over the past two decades in advancing imaging techniques and therapeutic strategies with a precise focus on targeting VSMCs within atherosclerotic plaques, notably spotlighting meticulously engineered nanoparticles as a promising avenue. We envision the potential of VSMC-targeted nanoparticles, thoughtfully loaded with medications or combination therapies, to effectively mitigate pro-atherogenic VSMC processes. These advancements are poised to contribute significantly to the pivotal objective of modulating VSMC phenotypes and enhancing plaque stability. Moreover, our paper also delves into recent breakthroughs in VSMC-targeted imaging technologies, showcasing their remarkable precision in locating microcalcifications, dynamically monitoring plaque fibrous cap integrity, and assessing the therapeutic efficacy of medical interventions. Lastly, we conscientiously explore the opportunities and challenges inherent in this innovative approach, providing a holistic perspective on the potential of VSMC-targeted strategies in the evolving landscape of atherosclerosis research and treatment.
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Affiliation(s)
- Jianhua He
- School of Pharmacy, Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China.
| | - Yu Gao
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Can Yang
- School of Pharmacy, Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Yujie Guo
- School of Pharmacy, Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Lisha Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| | - Shan Lu
- School of Pharmacy, Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China.
| | - Hongliang He
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, People's Republic of China.
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22
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Wang Y, Li M, Sheng Z, Ran H, Dong J, Fang L, Zhang P. Ultrasound-mediated delivery of Pik3cb shRNA using magnetic nanoparticles for the treatment of in-stent restenosis in a rat balloon-injured model. JOURNAL OF RADIATION RESEARCH 2024; 65:47-54. [PMID: 37948449 PMCID: PMC10803161 DOI: 10.1093/jrr/rrad083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/27/2023] [Indexed: 11/12/2023]
Abstract
The aim of the present work was to examine the effect of polyethylene glycol (PEG)-coated superparamagnetic iron oxide (SPIO) nanoparticles carrying Pik3cb short hairpin RNA (shRNA) in the prevention of restenosis with the aid of ultrasound and a magnetic field. SPIO is a type of contrast agent used in medical imaging to enhance the visibility of specific tissues or organs. It consists of tiny iron oxide nanoparticles that can be targeted to specific areas of interest in the body. PEG-coated SPIO nanoparticles carrying Pik3cb shRNA (SPIO-shPik3cb) were prepared, and the particle size and zeta potential of PEG-coated SPIO nanoparticles with and without Pik3cb shRNA were examined. After a right common artery balloon-injured rat model was established, the rats were randomly divided into four groups, and the injured arteries were transfected with SPIO-shPik3cb, saline, SPIO-shcontrol and naked shRNA Pik3cb. During the treatment, each group was placed under a magnetic field and was transfected with the aid of ultrasound. Rats were sacrificed, and the tissue was harvested for analysis after 14 days. The results suggested that the mean particle size and zeta potential of SPIO-shPik3cbs were 151.45 ± 11 nm and 10 mV, respectively. SPIO-shPik3cb showed higher transfection efficiency and significantly inhibited the intimal thickening compared with naked Pik3cb shRNA in vascular smooth muscle cells (VSMCs) (*P < 0.05). Moreover, SPIO-shPik3cb could also significantly downregulate the expression of pAkt protein compared with naked Pik3cb shRNA. According to the results, SPIO-shPik3cb can remarkably inhibit the intimal thickening under a combination of magnetic field exposure and ultrasound.
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Affiliation(s)
- Yuhao Wang
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
| | - Miao Li
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
| | - Zongxiang Sheng
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
| | - Hong Ran
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
| | - Jing Dong
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
| | - Lingling Fang
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
| | - Pingyang Zhang
- Department of Cardiovascular Ultrasound, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China
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23
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Zhu G, Gao H, Li Y, Li X, Yang X, Wang C, Guo Z, Fan H, Fan L. Suppression of endoplasmic reticulum stress by 4-PBA enhanced atherosclerotic plaque stability via up-regulating CLOCK expression. Pathol Res Pract 2024; 253:154969. [PMID: 38029715 DOI: 10.1016/j.prp.2023.154969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/01/2023]
Abstract
Endoplasmic reticulum (ER) stress refers to a condition where the normal functioning of the ER is disrupted due to a variety of cellular stress factors. As a result, there is an accumulation of unfolded and misfolded proteins within the ER. Numerous studies have shown that ER stress can exacerbate inflammatory reactions and contribute to the development of various inflammatory diseases. However, the role of ER stress in the stability of atherosclerotic plaques remains poorly understood. In this study, we aimed to explore the potential impact of a specific ER stress inhibitor known as 4-phenyl butyric acid (4-PBA) on atherosclerosis in mice. The mice were fed a high-fat diet, and treatment with 4-PBA significantly improved the stability of the atherosclerotic plaques. This was evidenced by a reduction in oxidative stress and an increase in circadian locomotor output cycles kaput (CLOCK) protein and mRNA expression within the plaques. Additionally, 4-PBA reduced the expression of ER stress-related proteins and decreased apoptosis in the atherosclerotic plaques. In vitro investigation, we observed the effect of 4-PBA on vascular smooth muscle cells (VSMCs) that were exposed to oxidized low-density lipoprotein (ox-LDL), a significant contributor to the development of atherosclerosis. 4-PBA reduced reactive oxygen species (ROS) production and attenuated apoptosis, GRP78 and CHOP protein expression in ox-LDL-Induced VSMCs via up-regulating CLOCK expression. However, when the short hairpin RNA against CLOCK (sh-CLOCK) was introduced to the VSMCs, the protective effect of 4-PBA was abolished. This suggests that the up-regulation of CLOCK expression is crucial for the beneficial effects of 4-PBA on atherosclerotic plaque stability. This finding suggests that targeting ER stress and modulating CLOCK protein levels might be a promising way to enhance the stability of atherosclerotic plaques.
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Affiliation(s)
- Guanglang Zhu
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongxia Gao
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Li
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xu Li
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaohu Yang
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chen Wang
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenyu Guo
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Heyu Fan
- School of Arts and Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Longhua Fan
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China; Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
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24
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Zhao L, Ma D, Wang L, Su X, Feng L, Zhu L, Chen Y, Hao Y, Wang X, Feng J. Metabolic changes with the occurrence of atherosclerotic plaques and the effects of statins. Front Immunol 2023; 14:1301051. [PMID: 38143759 PMCID: PMC10739339 DOI: 10.3389/fimmu.2023.1301051] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/23/2023] [Indexed: 12/26/2023] Open
Abstract
Atherosclerosis is a common cardiovascular disease caused by the abnormal expression of multiple factors and genes influenced by both environmental and genetic factors. The primary manifestation of atherosclerosis is plaque formation, which occurs when inflammatory cells consume excess lipids, affecting their retention and modification within the arterial intima. This triggers endothelial cell (EC) activation, immune cell infiltration, vascular smooth muscle cell (VSMC) proliferation and migration, foam cell formation, lipid streaks, and fibrous plaque development. These processes can lead to vascular wall sclerosis, lumen stenosis, and thrombosis. Immune cells, ECs, and VSMCs in atherosclerotic plaques undergo significant metabolic changes and inflammatory responses. The interaction of cytokines and chemokines secreted by these cells leads to the onset, progression, and regression of atherosclerosis. The regulation of cell- or cytokine-based immune responses is a novel therapeutic approach for atherosclerosis. Statins are currently the primary pharmacological agents utilised for managing unstable plaques owing to their ability to enhance endothelial function, regulate VSMC proliferation and apoptosis by reducing cholesterol levels, and mitigate the expression and activity of inflammatory cytokines. In this review, we provide an overview of the metabolic changes associated with atherosclerosis, describe the effects of inflammatory responses on atherosclerotic plaques, and discuss the mechanisms through which statins contribute to plaque stabilisation. Additionally, we examine the role of statins in combination with other drugs in the management of atherosclerosis.
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Affiliation(s)
| | - Di Ma
- Bethune First Hospital, Jilin University, Changchun, China
| | - LiJuan Wang
- Bethune First Hospital, Jilin University, Changchun, China
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25
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Gellhaus B, Böker KO, Schilling AF, Saul D. Therapeutic Consequences of Targeting the IGF-1/PI3K/AKT/FOXO3 Axis in Sarcopenia: A Narrative Review. Cells 2023; 12:2787. [PMID: 38132107 PMCID: PMC10741475 DOI: 10.3390/cells12242787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
The high prevalence of sarcopenia in an aging population has an underestimated impact on quality of life by increasing the risk of falls and subsequent hospitalization. Unfortunately, the application of the major established key therapeutic-physical activity-is challenging in the immobile and injured sarcopenic patient. Consequently, novel therapeutic directions are needed. The transcription factor Forkhead-Box-Protein O3 (FOXO3) may be an option, as it and its targets have been observed to be more highly expressed in sarcopenic muscle. In such catabolic situations, Foxo3 induces the expression of two muscle specific ubiquitin ligases (Atrogin-1 and Murf-1) via the PI3K/AKT pathway. In this review, we particularly evaluate the potential of Foxo3-targeted gene therapy. Foxo3 knockdown has been shown to lead to increased muscle cross sectional area, through both the AKT-dependent and -independent pathways and the reduced impact on the two major downstream targets Atrogin-1 and Murf-1. Moreover, a Foxo3 reduction suppresses apoptosis, activates satellite cells, and initiates their differentiation into muscle cells. While this indicates a critical role in muscle regeneration, this mechanism might exhaust the stem cell pool, limiting its clinical applicability. As systemic Foxo3 knockdown has also been associated with risks of inflammation and cancer progression, a muscle-specific approach would be necessary. In this review, we summarize the current knowledge on Foxo3 and conceptualize a specific and targeted therapy that may circumvent the drawbacks of systemic Foxo3 knockdown. This approach presumably would limit the side effects and enable an activity-independent positive impact on skeletal muscle.
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Affiliation(s)
- Benjamin Gellhaus
- Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August University of Goettingen, 37075 Goettingen, Germany; (B.G.); (K.O.B.); (A.F.S.)
| | - Kai O. Böker
- Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August University of Goettingen, 37075 Goettingen, Germany; (B.G.); (K.O.B.); (A.F.S.)
| | - Arndt F. Schilling
- Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August University of Goettingen, 37075 Goettingen, Germany; (B.G.); (K.O.B.); (A.F.S.)
| | - Dominik Saul
- Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August University of Goettingen, 37075 Goettingen, Germany; (B.G.); (K.O.B.); (A.F.S.)
- Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tuebingen, BG Trauma Center Tuebingen, 72072 Tuebingen, Germany
- Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
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26
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Yang C, Mu Y, Li S, Zhang Y, Liu X, Li J. Tanshinone IIA: a Chinese herbal ingredient for the treatment of atherosclerosis. Front Pharmacol 2023; 14:1321880. [PMID: 38108067 PMCID: PMC10722201 DOI: 10.3389/fphar.2023.1321880] [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: 10/15/2023] [Accepted: 11/21/2023] [Indexed: 12/19/2023] Open
Abstract
Tanshinone IIA (Tan IIA) is a fat-soluble compound extracted from Salvia miltiorrhiza, which has a protective effect against atherosclerosis (AS). Tan IIA can inhibit oxidative stress and inflammatory damage of vascular endothelial cells (VECs) and improve endothelial cell dysfunction. Tan IIA also has a good protective effect on vascular smooth muscle cells (VSMCs). It can reduce vascular stenosis by inhibiting the proliferation and migration of vascular smooth muscle cells (VSMCs), and improve the stability of the fibrous cap of atherosclerotic plaque by inhibiting apoptosis and inflammation of VSMCs. In addition, Tan IIA inhibits the inflammatory response of macrophages and the formation of foam cells in atherosclerotic plaques. In summary, Tan IIA improves AS through a complex pathway. We propose to further study the specific molecular targets of Tan IIA using systems biology methods, so as to fundamentally elucidate the mechanism of Tan IIA. It is worth mentioning that there is a lack of high-quality evidence-based medical data on Tan IIA treatment of AS. We recommend that a randomized controlled clinical trial be conducted to evaluate the exact efficacy of Tan IIA in improving AS. Finally, sodium tanshinone IIA sulfonate (STS) can cause adverse drug reactions in some patients, which needs our attention.
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Affiliation(s)
- Chunkun Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | | | - Shuanghong Li
- Weifang Hospital of Traditional Chinese Medicine, Weifang, China
| | - Yang Zhang
- Weifang People’s Hospital, Weifang, China
| | - Xiaoyuan Liu
- Weifang Hospital of Traditional Chinese Medicine, Weifang, China
| | - Jun Li
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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27
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Luo L, Fu C, Bell CF, Wang Y, Leeper NJ. Role of vascular smooth muscle cell clonality in atherosclerosis. Front Cardiovasc Med 2023; 10:1273596. [PMID: 38089777 PMCID: PMC10713728 DOI: 10.3389/fcvm.2023.1273596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/24/2023] [Indexed: 02/01/2024] Open
Abstract
Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. While many cell types contribute to the growing atherosclerotic plaque, the vascular smooth muscle cell (SMC) is a major contributor due in part to its remarkable plasticity and ability to undergo phenotype switching in response to injury. SMCs can migrate into the fibrous cap, presumably stabilizing the plaque, or accumulate within the lesional core, possibly accelerating vascular inflammation. How SMCs expand and react to disease stimuli has been a controversial topic for many decades. While early studies relying on X-chromosome inactivation were inconclusive due to low resolution and sensitivity, recent advances in multi-color lineage tracing models have revitalized the concept that SMCs likely expand in an oligoclonal fashion during atherogenesis. Current efforts are focused on determining whether all SMCs have equal capacity for clonal expansion or if a "stem-like" progenitor cell may exist, and to understand how constituents of the clone decide which phenotype they will ultimately adopt as the disease progresses. Mechanistic studies are also beginning to dissect the processes which confer cells with their overall survival advantage, test whether these properties are attributable to intrinsic features of the expanding clone, and define the role of cross-talk between proliferating SMCs and other plaque constituents such as neighboring macrophages. In this review, we aim to summarize the historical perspectives on SMC clonality, highlight unanswered questions, and identify translational issues which may need to be considered as therapeutics directed against SMC clonality are developed as a novel approach to targeting atherosclerosis.
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Affiliation(s)
- Lingfeng Luo
- Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
| | - Changhao Fu
- Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
| | - Caitlin F. Bell
- Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Nicholas J. Leeper
- Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
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28
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Cheng DCY, Climie RE, Shu M, Grieve SM, Kozor R, Figtree GA. Vascular aging and cardiovascular disease: pathophysiology and measurement in the coronary arteries. Front Cardiovasc Med 2023; 10:1206156. [PMID: 38089775 PMCID: PMC10715672 DOI: 10.3389/fcvm.2023.1206156] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 11/13/2023] [Indexed: 11/29/2024] Open
Abstract
Age is a key risk factor for cardiovascular disease, including atherosclerosis. However, pathophysiological disease processes in the arteries are not an inevitable feature of aging. Large cohort studies with arterial phenotyping along with clinical and demographic data are essential to better understand factors related to the susceptibility or resilience to age-related vascular pathophysiology in humans. This review explores the mechanisms by which vascular structure and function alters with age, and how these changes relate to cardiovascular pathophysiology and disease. Features of vascular aging in the coronary arteries have historically been difficult to quantify pre-mortem due to their size and location. However, non-invasive imaging modalities including CT Coronary Angiogram are now being used to assess coronary vascular age, and further advances in imaging analysis such as the CT Fat Attenuation Index will help provide further measurement of features associated with coronary vascular aging. Currently, markers of vascular aging are not used as therapeutic targets in routine clinical practice, but non-pharmacological interventions including aerobic exercise and low salt diet, as well as anti-hypertensives have been demonstrated to reduce arterial stiffness. Advances in imaging technology, both in acquisition and advanced analysis, as well as harmonisation of measurements for researchers across the globe will be invaluable in understanding what constitutes healthy vascular aging and in identifying features of vascular aging that are associated with coronary artery disease and its adverse outcomes. Assessing such images in large cohorts can facilitate improved definitions of resilient and susceptible phenotypes to vascular aging in the coronary arteries. This is a critical step in identifying further risk factors and biomarkers within these groups and driving forward the development of novel therapies aimed at slowing or stopping age-related vascular changes in the coronary arteries.
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Affiliation(s)
- Daniel C. Y. Cheng
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Rachel E. Climie
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Matthew Shu
- Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Stuart M. Grieve
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
- Imaging and Phenotyping Laboratory, Charles Perkins Centre and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Rebecca Kozor
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
- Department of Cardiology, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Gemma A. Figtree
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
- Imaging and Phenotyping Laboratory, Charles Perkins Centre and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Department of Cardiology, Royal North Shore Hospital, Sydney, NSW, Australia
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29
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Yogendran V, Mele L, Prysyazhna O, Budhram-Mahadeo VS. Vascular dysfunction caused by loss of Brn-3b/POU4F2 transcription factor in aortic vascular smooth muscle cells is linked to deregulation of calcium signalling pathways. Cell Death Dis 2023; 14:770. [PMID: 38007517 PMCID: PMC10676411 DOI: 10.1038/s41419-023-06306-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 09/14/2023] [Accepted: 11/07/2023] [Indexed: 11/27/2023]
Abstract
Phenotypic and functional changes in vascular smooth muscle cells (VSMCs) contribute significantly to cardiovascular diseases (CVD) but factors driving early adverse vascular changes are poorly understood. We report on novel and important roles for the Brn-3b/POU4F2 (Brn-3b) transcription factor (TF) in controlling VSMC integrity and function. Brn-3b protein is expressed in mouse aorta with localisation to VSMCs. Male Brn-3b knock-out (KO) aortas displayed extensive remodelling with increased extracellular matrix (ECM) deposition, elastin fibre disruption and small but consistent narrowing/coarctation in the descending aortas. RNA sequencing analysis showed that these effects were linked to deregulation of genes required for calcium (Ca2+) signalling, vascular contractility, sarco-endoplasmic reticulum (S/ER) stress responses and immune function in Brn-3b KO aortas and validation studies confirmed changes in Ca2+ signalling genes linked to increased intracellular Ca2+ and S/ER Ca2+ depletion [e.g. increased, Cacna1d Ca2+ channels; ryanodine receptor 2, (RyR2) and phospholamban (PLN) but reduced ATP2a1, encoding SERCA1 pump] and chaperone proteins, Hspb1, HspA8, DnaJa1 linked to increased S/ER stress, which also contributes to contractile dysfunction. Accordingly, vascular rings from Brn-3b KO aortas displayed attenuated contractility in response to KCl or phenylephrine (PE) while Brn-3b KO-derived VSMC displayed abnormal Ca2+ signalling following ATP stimulation. This data suggests that Brn-3b target genes are necessary to maintain vascular integrity /contractile function and deregulation upon loss of Brn-3b will contribute to contractile dysfunction linked to CVD.
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Affiliation(s)
- Vaishaali Yogendran
- Molecular Biology Development and Disease, UCL Institute of Cardiovascular Science, London, UK
| | - Laura Mele
- Molecular Biology Development and Disease, UCL Institute of Cardiovascular Science, London, UK
| | - Oleksandra Prysyazhna
- Clinical Pharmacology Centre, William Harvey Research Institute, Queen Mary University of London, London, UK
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30
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Liu QJ, Yuan W, Yang P, Shao C. Role of glycolysis in diabetic atherosclerosis. World J Diabetes 2023; 14:1478-1492. [PMID: 37970130 PMCID: PMC10642412 DOI: 10.4239/wjd.v14.i10.1478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/16/2023] [Accepted: 09/14/2023] [Indexed: 10/09/2023] Open
Abstract
Diabetes mellitus is a kind of typical metabolic disorder characterized by elevated blood sugar levels. Atherosclerosis (AS) is one of the most common complications of diabetes. Modern lifestyles and trends that promote overconsumption and unhealthy practices have contributed to an increase in the annual incidence of diabetic AS worldwide, which has created a heavy burden on society. Several studies have shown the significant effects of glycolysis-related changes on the occurrence and development of diabetic AS, which may serve as novel thera-peutic targets for diabetic AS in the future. Glycolysis is an important metabolic pathway that generates energy in various cells of the blood vessel wall. In particular, it plays a vital role in the physiological and pathological activities of the three important cells, Endothelial cells, macrophages and vascular smooth muscle cells. There are lots of similar mechanisms underlying diabetic and common AS, the former is more complex. In this article, we describe the role and mechanism underlying glycolysis in diabetic AS, as well as the therapeutic targets, such as trained immunity, microRNAs, gut microbiota, and associated drugs, with the aim to provide some new perspectives and potentially feasible programs for the treatment of diabetic AS in the foreseeable future.
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Affiliation(s)
- Qian-Jia Liu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Ping Yang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
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Yuwen Y, Wang X, Liu J, Liu Z, Zhu H. Delta- like ligand 4- expressing macrophages and human diseases: Insights into pathophysiology and therapeutic opportunities. Heliyon 2023; 9:e20777. [PMID: 37842562 PMCID: PMC10569996 DOI: 10.1016/j.heliyon.2023.e20777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/20/2023] [Accepted: 10/06/2023] [Indexed: 10/17/2023] Open
Abstract
Macrophages are key players in the immune response and have been implicated in various human diseases, including atherosclerosis, cancer, and chronic inflammatory disorders. While numerous studies have delved into the nuances of macrophage behavior in these conditions, there remains a gap in understanding the specific role of Delta-like ligand 4 (Dll4)-expressing macrophages and their overarching implications across these diseases. Among the plethora of factors expressed by macrophages, Dll4 has emerged as a molecule of particular interest. Recent studies have highlighted its unique role in modulating macrophage functions and its potential implications in various diseases. This review seeks to consolidate existing knowledge, address this gap, and present a comprehensive overview of Dll4-expressing macrophages in the context of these disorders and highlight their potential as therapeutic targets. We examined the involvement of Dll4-expressing macrophages in multiple human diseases such as atherosclerosis, cancer and chronic inflammatory diseases, emphasizing their influence on disease progression. We also discussed the challenges, limitations, and emerging research areas in targeting Dll4-expressing macrophages and provide an outlook on potential therapeutic strategies for the treatment of these diseases. By addressing the previously existing research gap, we've provided a roadmap that brings together fragmented insights, paving the way for more holistic research and potentially more effective therapeutic strategies centered on Dll4-expressing macrophages.
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Affiliation(s)
- Ya Yuwen
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Medical School, Xizang Minzu University, Xianyang, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Jing Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Haitao Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an, China
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Karolczak K, Watala C. Estradiol as the Trigger of Sirtuin-1-Dependent Cell Signaling with a Potential Utility in Anti-Aging Therapies. Int J Mol Sci 2023; 24:13753. [PMID: 37762053 PMCID: PMC10530977 DOI: 10.3390/ijms241813753] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/01/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Aging entails the inevitable loss of the structural and functional integrity of cells and tissues during the lifetime. It is a highly hormone-dependent process; although, the exact mechanism of hormone involvement, including sex hormones, is unclear. The marked suppression of estradiol synthesis during menopause suggests that the hormone may be crucial in maintaining cell lifespan and viability in women. Recent studies also indicate that the same may be true for men. Similar anti-aging features are attributed to sirtuin 1 (SIRT1), which may possibly be linked at the molecular level with estradiol. This finding may be valuable for understanding the aging process, its regulation, and possible prevention against unhealthy aging. The following article summarizes the initial studies published in this field with a focus on age-associated diseases, like cancer, cardiovascular disease and atherogenic metabolic shift, osteoarthritis, osteoporosis, and muscle damage, as well as neurodegenerative and neuropsychiatric diseases.
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Affiliation(s)
- Kamil Karolczak
- Department of Haemostatic Disorders, Medical University of Lodz, ul. Mazowiecka 6/8, 92-215 Lodz, Poland;
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Lazzarato L, Bianchi L, Andolfo A, Granata A, Lombardi M, Sinelli M, Rolando B, Carini M, Corsini A, Fruttero R, Arnaboldi L. Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms. Molecules 2023; 28:5724. [PMID: 37570694 PMCID: PMC10420201 DOI: 10.3390/molecules28155724] [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: 05/30/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies. We therefore assessed whether this property is dependent on their thiol-induced ring opening. Indeed, while furazans (analogues unable to release NO) are not effective, furoxans' inhibitory potency parallels with the electron-attractor capacity of the group in 3 of the ring, making this effect tunable. To demonstrate whether their specific block on G1-S phase could be NO-dependent, we supplemented SMCs with furoxans and inhibitors of GMP- and/or of the polyamine pathway, which regulate NO-induced SMC proliferation, but they failed in preventing the antiproliferative effect. To find the real mechanism of this property, our proteomics studies revealed that eleven cellular proteins (with SUMO1 being central) and networks involved in cell homeostasis/proliferation are modulated by furoxans, probably by interaction with adducts generated after degradation. Altogether, thanks to their dual effect and pharmacological flexibility, furoxans may be evaluated in the future as antiatherosclerotic molecules.
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Affiliation(s)
- Loretta Lazzarato
- Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy; (L.L.); (B.R.); (R.F.)
| | - Laura Bianchi
- Functional Proteomics Laboratory, Department of Life Sciences, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy;
| | - Annapaola Andolfo
- Proteomics and Metabolomics Facility (ProMeFa), Center for Omics Sciences (COSR), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy;
| | - Agnese Granata
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (A.G.); (M.L.); (M.S.); (A.C.)
| | - Matteo Lombardi
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (A.G.); (M.L.); (M.S.); (A.C.)
| | - Matteo Sinelli
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (A.G.); (M.L.); (M.S.); (A.C.)
| | - Barbara Rolando
- Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy; (L.L.); (B.R.); (R.F.)
| | - Marina Carini
- Department of Pharmaceutical Sciences “Pietro Pratesi”, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy;
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (A.G.); (M.L.); (M.S.); (A.C.)
| | - Roberta Fruttero
- Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy; (L.L.); (B.R.); (R.F.)
| | - Lorenzo Arnaboldi
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (A.G.); (M.L.); (M.S.); (A.C.)
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Neels JG, Gollentz C, Chinetti G. Macrophage death in atherosclerosis: potential role in calcification. Front Immunol 2023; 14:1215612. [PMID: 37469518 PMCID: PMC10352763 DOI: 10.3389/fimmu.2023.1215612] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/20/2023] [Indexed: 07/21/2023] Open
Abstract
Cell death is an important aspect of atherosclerotic plaque development. Insufficient efferocytosis of death cells by phagocytic macrophages leads to the buildup of a necrotic core that impacts stability of the plaque. Furthermore, in the presence of calcium and phosphate, apoptotic bodies resulting from death cells can act as nucleation sites for the formation of calcium phosphate crystals, mostly in the form of hydroxyapatite, which leads to calcification of the atherosclerotic plaque, further impacting plaque stability. Excessive uptake of cholesterol-loaded oxidized LDL particles by macrophages present in atherosclerotic plaques leads to foam cell formation, which not only reduces their efferocytosis capacity, but also can induce apoptosis in these cells. The resulting apoptotic bodies can contribute to calcification of the atherosclerotic plaque. Moreover, other forms of macrophage cell death, such as pyroptosis, necroptosis, parthanatos, and ferroptosis can also contribute by similar mechanisms to plaque calcification. This review focuses on macrophage death in atherosclerosis, and its potential role in calcification. Reducing macrophage cell death and/or increasing their efferocytosis capacity could be a novel therapeutic strategy to reduce the formation of a necrotic core and calcification and thereby improving atherosclerotic plaque stability.
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Affiliation(s)
- Jaap G. Neels
- Université Côte d’Azur, Institut national de la santé et de la recherche médicale (INSERM), Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Claire Gollentz
- Université Côte d’Azur, Centre Hospitalier Universitaire (CHU), Institut national de la santé et de la recherche médicale (NSERM), Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Giulia Chinetti
- Université Côte d’Azur, Centre Hospitalier Universitaire (CHU), Institut national de la santé et de la recherche médicale (NSERM), Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
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Sun J, Singh P, Shami A, Kluza E, Pan M, Djordjevic D, Michaelsen NB, Kennbäck C, van der Wel NN, Orho-Melander M, Nilsson J, Formentini I, Conde-Knape K, Lutgens E, Edsfeldt A, Gonçalves I. Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture. J Am Coll Cardiol 2023; 81:2213-2227. [PMID: 37286250 DOI: 10.1016/j.jacc.2023.04.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/20/2023] [Accepted: 04/03/2023] [Indexed: 06/09/2023]
Abstract
BACKGROUND Atherosclerotic plaque ruptures, triggered by blood flow-associated biomechanical forces, cause most myocardial infarctions and strokes. OBJECTIVES This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. METHODS Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. RESULTS In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. CONCLUSIONS Our findings show plaque site-specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.
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Affiliation(s)
- Jiangming Sun
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Pratibha Singh
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Annelie Shami
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Ewelina Kluza
- Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam University Medical Center, Amsterdam, the Netherlands; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Mengyu Pan
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | | | - Natasha Barascuk Michaelsen
- Type 2 Diabetes and Cardiovascular Disease Research, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Cecilia Kennbäck
- Clinical Research Unit, Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
| | - Nicole N van der Wel
- Electron Microscopy Center Amsterdam, Department of Medical Biology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | | | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | | | | | - Esther Lutgens
- Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam University Medical Center, Amsterdam, the Netherlands; Cardiovascular Medicine, Experimental Cardiovascular Immunology Laboratory, Mayo Clinic, Rochester, Minnesota, USA; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Andreas Edsfeldt
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Cardiology, Skåne University Hospital, Malmö, Sweden; Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Isabel Gonçalves
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Cardiology, Skåne University Hospital, Malmö, Sweden.
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Vasamsetti SB, Natarajan N, Sadaf S, Florentin J, Dutta P. Regulation of cardiovascular health and disease by visceral adipose tissue-derived metabolic hormones. J Physiol 2023; 601:2099-2120. [PMID: 35661362 PMCID: PMC9722993 DOI: 10.1113/jp282728] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 05/04/2022] [Indexed: 11/08/2022] Open
Abstract
Visceral adipose tissue (VAT) is a metabolic organ known to regulate fat mass, and glucose and nutrient homeostasis. VAT is an active endocrine gland that synthesizes and secretes numerous bioactive mediators called 'adipocytokines/adipokines' into systemic circulation. These adipocytokines act on organs of metabolic importance like the liver and skeletal muscle. Multiple preclinical and in vitro studies showed strong evidence of the roles of adipocytokines in the regulation of metabolic disorders like diabetes, obesity and insulin resistance. Adipocytokines, such as adiponectin and omentin, are anti-inflammatory and have been shown to prevent atherogenesis by increasing nitric oxide (NO) production by the endothelium, suppressing endothelium-derived inflammation and decreasing foam cell formation. By inhibiting differentiation of vascular smooth muscle cells (VSMC) into osteoblasts, adiponectin and omentin prevent vascular calcification. On the other hand, adipocytokines like leptin and resistin induce inflammation and endothelial dysfunction that leads to vasoconstriction. By promoting VSMC migration and proliferation, extracellular matrix degradation and inflammatory polarization of macrophages, leptin and resistin increase the risk of atherosclerotic plaque vulnerability and rupture. Additionally, the plasma concentrations of these adipocytokines alter in ageing, rendering older humans vulnerable to cardiovascular disease. The disturbances in the normal physiological concentrations of these adipocytokines secreted by VAT under pathological conditions impede the normal functions of various organs and affect cardiovascular health. These adipokines could be used for both diagnostic and therapeutic purposes in cardiovascular disease.
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Affiliation(s)
- Sathish Babu Vasamsetti
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA 15213
- Pittsburgh VA Medical Center-University Drive, University Drive C, Pittsburgh, PA, USA
| | - Niranjana Natarajan
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA 15213
| | - Samreen Sadaf
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA 15213
- Pittsburgh VA Medical Center-University Drive, University Drive C, Pittsburgh, PA, USA
| | - Jonathan Florentin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA 15213
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA 15213
- Pittsburgh VA Medical Center-University Drive, University Drive C, Pittsburgh, PA, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA, 15213
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 15213
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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Zhang Y, Weng J, Huan L, Sheng S, Xu F. Mitophagy in atherosclerosis: from mechanism to therapy. Front Immunol 2023; 14:1165507. [PMID: 37261351 PMCID: PMC10228545 DOI: 10.3389/fimmu.2023.1165507] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 06/02/2023] Open
Abstract
Mitophagy is a type of autophagy that can selectively eliminate damaged and depolarized mitochondria to maintain mitochondrial activity and cellular homeostasis. Several pathways have been found to participate in different steps of mitophagy. Mitophagy plays a significant role in the homeostasis and physiological function of vascular endothelial cells, vascular smooth muscle cells, and macrophages, and is involved in the development of atherosclerosis (AS). At present, many medications and natural chemicals have been shown to alter mitophagy and slow the progression of AS. This review serves as an introduction to the field of mitophagy for researchers interested in targeting this pathway as part of a potential AS management strategy.
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Affiliation(s)
- Yanhong Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiajun Weng
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Clinical Medical School (Xiyuan), Peking University, Beijing, China
- Department of Integrated Traditional and Western Medicine, Peking University Health Science Center, Beijing, China
| | - Luyao Huan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Song Sheng
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengqin Xu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Traditional Chinese Medicine Clinical Medical School (Xiyuan), Peking University, Beijing, China
- Department of Integrated Traditional and Western Medicine, Peking University Health Science Center, Beijing, China
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Macvanin M, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. New insights on the cardiovascular effects of IGF-1. Front Endocrinol (Lausanne) 2023; 14:1142644. [PMID: 36843588 PMCID: PMC9947133 DOI: 10.3389/fendo.2023.1142644] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
INTRODUCTION Cardiovascular (CV) disorders are steadily increasing, making them the world's most prevalent health issue. New research highlights the importance of insulin-like growth factor 1 (IGF-1) for maintaining CV health. METHODS We searched PubMed and MEDLINE for English and non-English articles with English abstracts published between 1957 (when the first report on IGF-1 identification was published) and 2022. The top search terms were: IGF-1, cardiovascular disease, IGF-1 receptors, IGF-1 and microRNAs, therapeutic interventions with IGF-1, IGF-1 and diabetes, IGF-1 and cardiovascular disease. The search retrieved original peer-reviewed articles, which were further analyzed, focusing on the role of IGF-1 in pathophysiological conditions. We specifically focused on including the most recent findings published in the past five years. RESULTS IGF-1, an anabolic growth factor, regulates cell division, proliferation, and survival. In addition to its well-known growth-promoting and metabolic effects, there is mounting evidence that IGF-1 plays a specialized role in the complex activities that underpin CV function. IGF-1 promotes cardiac development and improves cardiac output, stroke volume, contractility, and ejection fraction. Furthermore, IGF-1 mediates many growth hormones (GH) actions. IGF-1 stimulates contractility and tissue remodeling in humans to improve heart function after myocardial infarction. IGF-1 also improves the lipid profile, lowers insulin levels, increases insulin sensitivity, and promotes glucose metabolism. These findings point to the intriguing medicinal potential of IGF-1. Human studies associate low serum levels of free or total IGF-1 with an increased risk of CV and cerebrovascular illness. Extensive human trials are being conducted to investigate the therapeutic efficacy and outcomes of IGF-1-related therapy. DISCUSSION We anticipate the development of novel IGF-1-related therapy with minimal side effects. This review discusses recent findings on the role of IGF-1 in the cardiovascular (CVD) system, including both normal and pathological conditions. We also discuss progress in therapeutic interventions aimed at targeting the IGF axis and provide insights into the epigenetic regulation of IGF-1 mediated by microRNAs.
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Affiliation(s)
- Mirjana Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Clinic for Internal Medicine, Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Xin Gao
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis. Cell Death Dis 2023; 9:49. [PMID: 36750553 PMCID: PMC9905587 DOI: 10.1038/s41420-023-01305-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/23/2022] [Accepted: 01/05/2023] [Indexed: 02/09/2023]
Abstract
Neointima lesion and atherosclerosis are proliferative vascular diseases associated with deregulated proliferation of vascular smooth muscle cells (SMCs). CFI-400945 is a novel, highly effective anticancer drug that inhibits polo-like kinase 4 (PLK4) and targets mitosis. In this study, we aim to investigate how CFI-400945 affects the development of proliferative vascular diseases. In C57BL/6 mice, neointima formation was generated by complete carotid ligation. In apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet, atherosclerosis was induced by partial carotid ligation. CFI-400945 was directly applied to carotid arteries via a perivascular collar. Our results showed that CFI-400945 drastically inhibited neointima formation but significantly accelerated atherosclerosis. In vitro studies showed that CFI-400945 treatment induced SMC polyploidization and arrested cells in the G2/M phase. CFI-400945 treatment upregulated p53 and p27 expression but decreased p21 and cyclin B1 expression. CFI-400945 also induced SMC apoptosis, which was inhibited by hydroxyurea, a DNA synthesis inhibitor that inhibits polyploidization. Furthermore, CFI-400945 caused supernumerary centrosomes, leading to mitotic failure, resulting in polyploidization. In conclusion, CFI-400945 prevents carotid arterial neointima formation in C57BL/6 mice but accelerates atherosclerosis in ApoE-/- mice, likely through mitotic arrest and subsequent induction of polyploidization and apoptosis.
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40
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Millet shell polyphenols ameliorate atherosclerosis development by suppressing foam cell formation. J Nutr Biochem 2023; 115:109271. [PMID: 36657531 DOI: 10.1016/j.jnutbio.2023.109271] [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: 06/18/2022] [Revised: 12/12/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
Polyphenols are bioactive compounds that occur naturally in plants, and they are widely used for disease prevention and health maintenance. In present study, the effects of millet shell polyphenols (MSPs) in thwarting atherosclerosis were explored. The results found that MSPs effectively inhibited the ability of macrophages to phagocytose lipids, and reduced the secretion of inflammatory factors IL-1β and TNF-α by obstructing the expression of STAT3 and NF-κB in macrophages. Eventually, MSPs hindered the formation of macrophage-derived foam cells. On the other hand, MSPs promoted the transformation of HASMCs from synthesis to contraction by regulating the gene expression levels of smooth muscle myosin heavy chain (SMMHC), desmin (DES), smoothelin (SMTN) and elastin (ELN). Lipid phagocytosis inhibited along with this process, thereby reducing the formation of smooth muscle cell-derived foam cells. In addition, experiments in ApoE-/- mice also showed that MSPs increased high-density lipoprotein cholesterol (HDL-C). Collectively, MSPs play a role in preventing atherosclerosis by impeding foam cell production. This study offers an integrative strategy for thwarting plaque formation in the early stages of atherosclerosis in cardiovascular disease.
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Yanikoglu A. The Probable Role of Chlamydia pneumoniae Infection in Acute Stroke. Infect Dis (Lond) 2023. [DOI: 10.5772/intechopen.109582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Cardiovascular diseases are the most leading cause of worldwide mortality. According to USA statistics, about 1 of 6 cardiovascular deaths is due to stroke. Stroke is the second most common cause of death and a chief cause of disability due to EU data. Treatment, care providing, rehabilitation costs and with the labor loss, the overall cost in EU due to stroke was estimated about €45 billion in year 2017. Acute stroke due to infectious diseases via several possible mechanisms with various clinical presentations were previously reported in the literature. Chlamydia pneumoniae is an obligate intracellular bacteria and extremely common in adult individuals. Besides it being a major cause of pneumonia in adults, association between atherosclerosis and vascular diseases was demonstrated by several sero-epidemiological studies and by direct detection of organism in atherosclerotic lesions by electron microscopy, immunohistochemistry, polymerase chain reaction. Also, several sero-epidemiological studies have demonstrated a link between Chlamydia pneumoniae infection and acute stroke. In this chapter, we will summarize the data in literature regarding the association between Chlamydia pneumoniae infection and acute stroke and we will try to explain the possible mechanisms that could be responsible in pathophysiology of stroke in these patients.
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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.
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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:
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Jiang Y, Qian HY. Transcription factors: key regulatory targets of vascular smooth muscle cell in atherosclerosis. Mol Med 2023; 29:2. [PMID: 36604627 PMCID: PMC9817296 DOI: 10.1186/s10020-022-00586-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 12/05/2022] [Indexed: 01/07/2023] Open
Abstract
Atherosclerosis (AS), leading to gradual occlusion of the arterial lumen, refers to the accumulation of lipids and inflammatory debris in the arterial wall. Despite therapeutic advances over past decades including intervention or surgery, atherosclerosis is still the most common cause of cardiovascular diseases and the main mechanism of death and disability worldwide. Vascular smooth muscle cells (VSMCs) play an imperative role in the occurrence of atherosclerosis and throughout the whole stages. In the past, there was a lack of comprehensive understanding of VSMCs, but the development of identification technology, including in vivo single-cell sequencing technology and lineage tracing with the CreERT2-loxP system, suggests that VSMCs have remarkable plasticity and reevaluates well-established concepts about the contribution of VSMCs. Transcription factors, a kind of protein molecule that specifically recognizes and binds DNA upstream promoter regions or distal enhancer DNA elements, play a key role in the transcription initiation of the coding genes and are necessary for RNA polymerase to bind gene promoters. In this review, we highlight that, except for environmental factors, VSMC genes are transcriptionally regulated through complex interactions of multiple conserved cis-regulatory elements and transcription factors. In addition, through a series of transcription-related regulatory processes, VSMCs could undergo phenotypic transformation, proliferation, migration, calcification and apoptosis. Finally, enhancing or inhibiting transcription factors can regulate the development of atherosclerotic lesions, and the downstream molecular mechanism of transcriptional regulation has also been widely studied.
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Affiliation(s)
- Yu Jiang
- grid.506261.60000 0001 0706 7839Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037 China
| | - Hai-Yan Qian
- grid.506261.60000 0001 0706 7839Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037 China
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Gareev I, Kudriashov V, Sufianov A, Begliarzade S, Ilyasova T, Liang Y, Beylerli O. The role of long non-coding RNA ANRIL in the development of atherosclerosis. Noncoding RNA Res 2022; 7:212-216. [PMID: 36157350 PMCID: PMC9467859 DOI: 10.1016/j.ncrna.2022.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/22/2022] [Accepted: 09/01/2022] [Indexed: 11/28/2022] Open
Abstract
Atherosclerosis is an important pathological basis of coronary heart disease, and the antisense non-coding RNA in the INK4 locus (ANRIL) is located in the genetically susceptible segment with the strongest correlation with it - the short arm 2 region 1 of chromosome 9 (Chr9p21). ANRIL can produce linear, circular and other transcripts through different transcriptional splicing methods, which can regulate the proliferation and apoptosis of related cells and closely related to the development of atherosclerotic plaques. Linear ANRIL can regulate proliferation of vascular smooth muscle cells (VSMCs) in plaques by chromatin modification, as well as affecting on proliferation and the apoptosis of macrophages at the transcriptional level; circular ANRIL can affect on proliferation and apoptosis of VSMCs by chromatin modification as well as interfering with rRNA maturation. In this review we describe the evolutionary characteristics of ANRIL, the formation and structure of transcripts, and the mechanism by which each transcript regulates the proliferation and apoptosis of vascular cells and then participates in atherosclerosis.
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Affiliation(s)
- Ilgiz Gareev
- Educational and Scientific Institute of Neurosurgery, Рeoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
| | | | - Albert Sufianov
- Educational and Scientific Institute of Neurosurgery, Рeoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation.,Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Sema Begliarzade
- Republican Clinical Perinatal Center, Republic of Bashkortostan, 450106, Russia
| | - Tatiana Ilyasova
- Department of Internal Diseases, Bashkir State Medical University, Republic of Bashkortostan, Ufa, 450008, Russia
| | - Yanchao Liang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Ozal Beylerli
- Educational and Scientific Institute of Neurosurgery, Рeoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
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Rai V, Singh H, Agrawal DK. Targeting the Crosstalk of Immune Response and Vascular Smooth Muscle Cells Phenotype Switch for Arteriovenous Fistula Maturation. Int J Mol Sci 2022; 23:12012. [PMID: 36233314 PMCID: PMC9570261 DOI: 10.3390/ijms231912012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated by innate and adaptive immune response involving infiltration of immune cells and secretion of pro- and anti-inflammatory cytokines. Impaired immune cell infiltration and change in vascular smooth muscle cell (VSMC) phenotype play a crucial role in the underlying pathophysiology. However, the change in the phenotype of VSMCs in a microenvironment of immune cell infiltration and increased secretion of cytokines have not been investigated. Since change in VSMC phenotype regulates vessel remodeling after intimal injury, in this study, we investigated the effect of macrophages and pro-inflammatory cytokines, IL-6, IL-1β, and TNF-α, on the change in VSMC phenotype under in vitro conditions. We also investigated the expression of the markers of VSMC phenotypes in arteries with atherosclerotic plaques and VSMCs isolated from control arteries. We found that the inhibition of cytokine downstream signaling may mitigate the effect of cytokines on the change in VSMCs phenotype. The results of this study support that regulating or targeting immune cell infiltration and function might be a therapeutic strategy to mitigate the effects of chronic inflammation to attenuate plaque formation, early thrombosis, and stenosis, and thus enhance AVF maturation.
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Affiliation(s)
| | | | - Devendra K. Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
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LncRNA MDRL Mitigates Atherosclerosis through miR-361/SQSTM1/NLRP3 Signaling. Mediators Inflamm 2022; 2022:5463505. [PMID: 36186576 PMCID: PMC9519314 DOI: 10.1155/2022/5463505] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 07/25/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
Objective Long non-coding RNAs (lncRNAs) play many important roles in gene regulation and disease pathogenesis. Here, we sought to determine that mitochondrial dynamic related lncRNA (MDRL) modulates NLRP3 inflammasome activation and apoptosis of vascular smooth muscle cells (VSMCs) and protects arteries against atherosclerosis. Methods In vivo experiments, we applied LDLR knockout (LDLR−/−) mice fed the high-fat diet to investigate the effects of MDRL on atherosclerosis. In vitro experiments, we applied mouse aortic smooth muscle cells to determine the mechanism of MDRL in abrogating NLRP3 inflammasome and inhibiting cell apoptosis through miR-361/sequentosome 1 (SQSTM1) by TUNEL staining, quantitative RT-PCR, western blot, microribonucleoprotein immunoprecipitation, and luciferase reporter assay. Results Downregulated MDRL and increased NLRP3 were observed in mouse atherosclerotic plaques, accompanied with the increase of miR-361. The results showed that MDRL overexpression significantly attenuated the burden of atherosclerotic plaque and facilitated plaque stability through inhibiting NLRP3 inflammasome activation and cell apoptosis, and vice versa. Mechanically, MDRL suppressed NLRP3 inflammasome activation and VSMC apoptosis via suppressing miR-361. Furthermore, miR-361 directly bound to the 3'UTR of SQSTM1 and inhibited its translation, subsequently activating NLRP3 inflammasome. Systematic delivery of miR-361 partly counteracted the beneficial effects of MDRL overexpression on atherosclerotic development in LDLR−/− mice. Conclusions In summary, MDRL alleviates NLRP3 inflammasome activation and apoptosis in VSMCs through miR-361/SQSTM1/NLRP3 pathway during atherogenesis. These data indicate that MDRL and inhibition of miR-361 represent potential therapeutic targets in atherosclerosis-related diseases.
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Zhang X, Ren Z, Jiang Z. EndMT-derived mesenchymal stem cells: a new therapeutic target to atherosclerosis treatment. Mol Cell Biochem 2022; 478:755-765. [PMID: 36083511 DOI: 10.1007/s11010-022-04544-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/12/2022] [Indexed: 11/28/2022]
Abstract
Cardiovascular diseases, such as coronary artery disease and stroke, are the main threats to human health worldwide. Atherosclerosis, a chronic inflammatory disorder, plays a role as an initiator of all of the above-mentioned diseases. Cell therapy for diseases has attracted widespread attention. Mesenchymal stem cells (MSCs) are a type of stem cell that still exist in adults and have the characteristics of self-renewal ability, pluripotent differentiation potential, immunomodulation, tissue regeneration, anti-inflammation and low immunogenicity. In light of the properties of MSCs, some researchers have begun to target MSCs to create a possible way to alleviate atherosclerosis. Most of these studies are focused on MSC transplantation, injecting MSCs to modulate macrophages, the key inflammatory cell in atherosclerosis plaque. According to recent studies, researchers found that endothelial-to-mesenchymal transition (EndMT) has something to do with atherosclerosis development. A new cell type MSC might also appear during the EndMT process. In this article, we summarize the characteristics of MSCs, the latest progress of MSC research and its application prospects, and in view of the process of EndMT occurring in atherosclerosis, we propose some new ideas for the treatment of atherosclerosis by targeting MSCs.
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Affiliation(s)
- Xiaofan Zhang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhisheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China.
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48
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Chen Y, Qin W, Li L, Wu P, Wei D. Mitophagy: Critical Role in Atherosclerosis Progression. DNA Cell Biol 2022; 41:851-860. [PMID: 36036955 DOI: 10.1089/dna.2022.0249] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Autophagy maintains intracellular homeostasis in the cardiovascular system, including in cardiomyocytes, endothelial cells (ECs), and arterial smooth muscle cells. Mitophagy, a selective autophagy that specifically removes damaged and dysfunctional mitochondria, is particularly important for cardiovascular homeostasis. Dysfunctional mitophagy contributes to cardiovascular disease, particularly atherosclerosis (AS). This review focuses on the advances of regulator mechanisms of mitophagy and its potential roles in AS. The findings are beneficial to understanding the pathological processes of atherosclerotic lesions and provide new ideas for the prevention and clinical treatment of AS.
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Affiliation(s)
- Yanmei Chen
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Wenhua Qin
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Lu Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Peng Wu
- Yueyang Maternal-Child Medicine Health Hospital Hunan, Province Innovative Training Base for Medical Postgraduates, University of China South China and Yueyang Women & Children's Medical Center, Yueyang, China.,Hengyang Maternal and Child Health Hospital, Hengyang, China
| | - Dangheng Wei
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China.,Yueyang Maternal-Child Medicine Health Hospital Hunan, Province Innovative Training Base for Medical Postgraduates, University of China South China and Yueyang Women & Children's Medical Center, Yueyang, China
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Cao S, Yuan Q, Dong Q, Liu X, Liu W, Zhai X, Zhang C, Liu H, Tang M, Wei S, Chen Y. Activin receptor-like kinase 7 promotes apoptosis of vascular smooth muscle cells via activating Smad2/3 signaling in diabetic atherosclerosis. Front Pharmacol 2022; 13:926433. [PMID: 36059980 PMCID: PMC9428160 DOI: 10.3389/fphar.2022.926433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) is a vital accelerator in the late phase of diabetic atherosclerosis, but the underlying mechanism remains unclear. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 pathway plays an important role in VSMC apoptosis of diabetic atherosclerosis. It was shown that ALK7 expression was obviously elevated in the aorta of ApoE−/− mice with type 2 diabetes mellitus. Inhibition of ALK7 expression significantly improved the stability of atherosclerotic plaques and reduced cell apoptosis. Further experiments showed that ALK7 knockdown stabilized atherosclerotic plaques by reducing VSMC apoptosis via activating Smad2/3. Our study uncovered the important role of ALK7-Smad2/3 signaling in VSMCs apoptosis, which might be a potential therapeutic target in diabetic atherosclerosis.
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Affiliation(s)
- Shengchuan Cao
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Qiuhuan Yuan
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Qianqian Dong
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xilong Liu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Weikang Liu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoxuan Zhai
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Chuanxin Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Han Liu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Mengxiong Tang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- *Correspondence: Yuguo Chen, ; Shujian Wei, ; Mengxiong Tang,
| | - Shujian Wei
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- *Correspondence: Yuguo Chen, ; Shujian Wei, ; Mengxiong Tang,
| | - Yuguo Chen
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- *Correspondence: Yuguo Chen, ; Shujian Wei, ; Mengxiong Tang,
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Bazan HA, Brooks AJ, Vongbunyong K, Tee C, Douglas HF, Klingenberg NC, Woods TC. A pro-inflammatory and fibrous cap thinning transcriptome profile accompanies carotid plaque rupture leading to stroke. Sci Rep 2022; 12:13499. [PMID: 35931792 PMCID: PMC9356141 DOI: 10.1038/s41598-022-17546-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Atherosclerotic plaque rupture is the etiology of ischemic stroke and myocardial infarction. The molecular mechanisms responsible for rupture remain unclear, in part, due to the lack of data from plaques at the time of rupture. Ribosome-depleted total RNA was sequenced from carotid plaques obtained from patients undergoing carotid endarterectomy with high-grade stenosis and either (1) a carotid-related ischemic cerebrovascular event within the previous 5 days ('recently ruptured,' n = 6) or (2) an absence of a cerebrovascular event ('asymptomatic,' n = 5). Principal component analysis confirmed plaque rupture was responsible for the greatest percentage of the variability between samples (23.2%), and recently ruptured plaques were enriched for transcripts associated with inflammation and extracellular matrix degradation. Hierarchical clustering achieved differentiation of the asymptomatic from the recently ruptured plaques. This analysis also found co-expression of transcripts for immunoglobulins and B lymphocyte function, matrix metalloproteinases, and interferon response genes. Examination of the differentially expressed genes supported the importance of inflammation and inhibition of proliferation and migration coupled with an increase in apoptosis. Thus, the transcriptome of recently ruptured plaques is enriched with transcripts associated with inflammation and fibrous cap thinning and support further examination of the role of B lymphocytes and interferons in atherosclerotic plaque rupture.
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Affiliation(s)
- Hernan A Bazan
- Section of Vascular/Endovascular Surgery, Department of Surgery, Ochsner Clinic Foundation, New Orleans, LA, USA
- Faculty of Medicine, Ochsner Clinical School, The University of Queensland, New Orleans, LA, USA
| | - Ashton J Brooks
- Section of Vascular/Endovascular Surgery, Department of Surgery, Ochsner Clinic Foundation, New Orleans, LA, USA
- Departments of Physiology and Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
| | - Kenny Vongbunyong
- Departments of Physiology and Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
| | - Christin Tee
- Departments of Physiology and Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
| | - Hunter F Douglas
- Departments of Physiology and Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
| | - Natasha C Klingenberg
- Departments of Physiology and Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
| | - T Cooper Woods
- Departments of Physiology and Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA.
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