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1
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Bril M, Boesveld JN, Coelho-Rato LS, Sahlgren CM, Bouten CVC, Kurniawan NA. Dynamic substrate topographies drive actin- and vimentin-mediated nuclear mechanoprotection events in human fibroblasts. BMC Biol 2025; 23:94. [PMID: 40189524 PMCID: PMC11974106 DOI: 10.1186/s12915-025-02199-7] [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: 01/27/2025] [Accepted: 03/27/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Dynamic physical changes in the extracellular environment of living tissues present a mechanical challenge for resident cells that can lead to damage to the nucleus, genome, and DNA. Recent studies have started to uncover nuclear mechanoprotection mechanisms that prevent excessive mechanical deformations of the nucleus. Here, we hypothesized that dynamic topographical changes in the cellular environment can be mechanically transmitted to the nucleus and trigger nuclear mechanoprotection events. We tested this using a photoresponsive hydrogel whose surface topography can be reversibly changed on demand upon light illumination, allowing us to subject cells to recurring microscale topographical changes. RESULTS With each recurring topographical change, fibroblasts were found to increasingly compact and relocate their nuclei away from the dynamic regions of the hydrogel. These cell-scale reorganization events were accompanied by an increase of global histone acetylation and decreased methylation in cells on the dynamic topographies, resulting in a minimization of DNA strand breakage. We further found that these nuclear mechanoprotection events were mediated by both vimentin intermediate filaments and the actin cytoskeleton. CONCLUSIONS Together, these data reveal that fibroblasts actively protect their nuclei in the presence of dynamic topographical changes through cytoskeleton-mediated mechanisms. Broadly, these results stress the importance of gaining a deeper fundamental understanding of the cellular mechanoresponse under dynamically changing conditions.
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Affiliation(s)
- Maaike Bril
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Jules N Boesveld
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Leila S Coelho-Rato
- Faculty of Science and Engineering, Åbo Akademi University, 20520, Turku, Finland
| | - Cecilia M Sahlgren
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
- Faculty of Science and Engineering, Åbo Akademi University, 20520, Turku, Finland
| | - Carlijn V C Bouten
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
| | - Nicholas A Kurniawan
- Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands.
- Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands.
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2
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Chen LJ, Li JYS, Nguyen P, Norwich G, Wang Y, Teng D, Shiu YT, Shyy JYJ, Chien S. Pulsatile flow induces chromatin interaction with lamin-associated proteins to enrich H3K9 methylation in endothelial cells. Proc Natl Acad Sci U S A 2025; 122:e2424566122. [PMID: 40117319 PMCID: PMC11962468 DOI: 10.1073/pnas.2424566122] [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: 11/26/2024] [Accepted: 02/19/2025] [Indexed: 03/23/2025] Open
Abstract
Endothelial cells (ECs) are constantly exposed to hemodynamic forces, which play a crucial role in regulating EC functions. Pulsatile laminar shear stress (PS), representing atheroprotective flow, maintains the anti-inflammation and homeostatic phenotype of ECs, but the comprehensive mechanism underlying the PS-repression of inflammatory genes remains to be determined. In this study, we investigated the role of chromatin organization in mediating the effects of PS on inflammatory gene expression in ECs. We demonstrated that PS induced the expression of histone methyltransferase SUV39H1 to promote heterochromatin formation via H3K9 trimethylation (H3K9me3) enrichment, a hallmark gene repression mechanism. SUV39H1 interacts with lamin-associated proteins and facilitates the perinuclear localization of the H3K9me3-enrichment. Silencing the lamin-associated protein emerin (EMD) not only led to the reductions of cytoskeletal F-actin formation and perinuclear H3K9me3 enrichment; but also the impairment of PS-induced SUV39H1 expression, H3K9me3 enrichment at E-selectin and vascular cell adhesion molecule 1 loci to revert their PS-repressed expression. Hence, EMD acts as a hub to transmit mechanical cues from the cytoskeleton to the nucleus and recruits SUV39H1, which regulate nuclear organization, chromatin state, and gene expression. These results accentuate the critical role of nuclear architecture in mechanotransduction and EC responses to mechanical stimuli.
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Affiliation(s)
- Li-Jing Chen
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA92093
| | - Julie Yi-Shuan Li
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA92093
| | - Phu Nguyen
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA92093
| | - Gerard Norwich
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA92093
| | - Yingxiao Wang
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA90089
| | - Dayu Teng
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA92093
| | - Yan-Ting Shiu
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, UT84112
- Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT84112
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT84112
| | - John Y. J. Shyy
- Department of Medicine, University of California at San Diego, La Jolla, CA92093
| | - Shu Chien
- Department of Bioengineering, University of California at San Diego, La Jolla, CA92093
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA92093
- Department of Medicine, University of California at San Diego, La Jolla, CA92093
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3
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Zhao Y, Ehteramyan M, Li Y, Bai X, Huang L, Gao Y, Angbohang A, Yang X, Lynham S, Margariti A, Shah AM, Tao Y, Cai T, Li T, Zhang M, Zeng L. A novel nested gene Aff3ir participates in vascular remodeling by enhancing endothelial cell differentiation in mice. Genes Dis 2025; 12:101339. [PMID: 39830032 PMCID: PMC11742352 DOI: 10.1016/j.gendis.2024.101339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/10/2024] [Accepted: 05/07/2024] [Indexed: 01/21/2025] Open
Affiliation(s)
- Yue Zhao
- Department of Heart Center, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Mazdak Ehteramyan
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Yi Li
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Xuefeng Bai
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Lei Huang
- Department of Heart Center, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Yingtang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- Tianjin Institute of Hepatobiliary Disease, Nankai University Affiliated Third Centre Hospital, Tianjin 300170, China
| | - Angshumonik Angbohang
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Xiaoping Yang
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Steven Lynham
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Andriana Margariti
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom
| | - Ajay M. Shah
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Yaling Tao
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, China
| | - Ting Cai
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, China
| | - Tong Li
- Department of Heart Center, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- School of Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- Tianjin Institute of Hepatobiliary Disease, Nankai University Affiliated Third Centre Hospital, Tianjin 300170, China
| | - Min Zhang
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
| | - Lingfang Zeng
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London SE5 9NU, United Kingdom
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4
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Rehman M, Agarwal V, Chaudhary R, Kaushik AS, Srivastava S, Srivastava S, Kumar A, Singh S, Mishra V. Pharmacological inhibition of histone deacetylase alleviates chronic unpredictable stress induced atherosclerosis and endothelial dysfunction via upregulation of BDNF. Biochem Biophys Res Commun 2024; 735:150485. [PMID: 39098273 DOI: 10.1016/j.bbrc.2024.150485] [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: 06/02/2024] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Long-term stress is a significant risk factor for cardiovascular diseases, including atherosclerosis and endothelial dysfunction. Moreover, prolonged stress has shown to negatively regulate central BDNF expression. The role of central BDNF in CNS disorders is well studied until recently the peripheral BDNF was also found to be involved in endothelial function regulation and atherosclerosis. The peripheral BDNF and its role in chronic stress-induced atherosclerosis and endothelial dysfunction remain unclear. Therefore, we aimed to elucidate the role of BDNF and its modulation by the HDAC inhibitor valproic acid (VA) in chronic unpredictable stress (CUS)-induced atherosclerosis and endothelial dysfunction. We demonstrated that a 10-week CUS mouse model substantially decreases central and peripheral BDNF expression, resulting in enhanced serum lipid indices, plaque deposition, fibrosis, and CD68 expression in thoracic aortas. Further, parameters associated with endothelial dysfunction such as increased levels of endothelin-1 (ET-1), adhesion molecules like VCAM-1, M1 macrophage markers, and decreased M2 macrophage markers, eNOS expression, and nitrite levels in aortas, were also observed. VA (50 mg/kg, 14 days, i. p.) was administered to mice following 8 weeks of CUS exposure until the end of the experimental procedure. VA significantly prevented the decrease in BDNF, eNOS and nitrite levels, reduced lesion formation and fibrosis in thoracic aortas and increased ET-1, and VCAM-1 followed by M2 polarization in VA-treated mice. The study highlights the potential of epigenetic modulation of BDNF as a therapeutic target, in stress-induced cardiovascular pathologies and suggests that VA could be a promising agent for mitigating CUS-induced endothelial dysfunction and atherosclerosis by BDNF modulation.
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Affiliation(s)
- Mujeeba Rehman
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Vipul Agarwal
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Arjun Singh Kaushik
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Siddhi Srivastava
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Sukriti Srivastava
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Anand Kumar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Sanjay Singh
- Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India.
| | - Vikas Mishra
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India.
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5
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Yang H, Guo K, Ding P, Ning J, Zhang Y, Wang Y, Wang Z, Liu G, Shao C, Pan M, Ma Z, Yan X, Han J. Histone deacetylases: Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis. Genes Dis 2024; 11:101216. [PMID: 39281836 PMCID: PMC11396065 DOI: 10.1016/j.gendis.2024.101216] [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: 08/28/2023] [Revised: 12/20/2023] [Accepted: 01/04/2024] [Indexed: 09/18/2024] Open
Abstract
Histone deacetylases (HDACs) are proteases that play a key role in chromosome structural modification and gene expression regulation, and the involvement of HDACs in cancer, the nervous system, and the metabolic and immune system has been well reviewed. Our understanding of the function of HDACs in the vascular system has recently progressed, and a significant variety of HDAC inhibitors have been shown to be effective in the treatment of vascular diseases. However, few reviews have focused on the role of HDACs in the vascular system. In this study, the role of HDACs in the regulation of the vascular system mainly involving endothelial cells and vascular smooth muscle cells was discussed based on recent updates, and the role of HDACs in different vascular pathogenesis was summarized as well. Furthermore, the therapeutic effects and prospects of HDAC inhibitors were also addressed in this review.
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Affiliation(s)
- Hanyi Yang
- Department of Ophthalmology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
- Xi'an Medical University, Xi'an, Shaanxi 710086, China
| | - Kai Guo
- Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710068, China
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Peng Ding
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Jiayi Ning
- Department of Ophthalmology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
- Xi'an Medical University, Xi'an, Shaanxi 710086, China
| | - Yimeng Zhang
- Department of Ophthalmology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
- Xi'an Medical University, Xi'an, Shaanxi 710086, China
| | - Yuanyong Wang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Zhaoyang Wang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Guanglin Liu
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Changjian Shao
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Minghong Pan
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Zhiqiang Ma
- Department of Medical Oncology, Senior Department of Oncology, Chinese PLA General Hospital, The Fifth Medical Center, Beijing 100853, China
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
| | - Jing Han
- Department of Ophthalmology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi 710038, China
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6
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Zhang Y, Guan Z, Gong H, Ni Z, Xiao Q, Guo X, Xu Q. The Role of Progenitor Cells in the Pathogenesis of Arteriosclerosis. CARDIOLOGY DISCOVERY 2024; 4:231-244. [DOI: 10.1097/cd9.0000000000000130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The increasing incidence of arteriosclerosis has become a significant global health burden. Arteriosclerosis is characterized by the thickening and hardening of arterial walls, which can lead to the narrowing or complete blockage of blood vessels. However, the pathogenesis of the disease remains incompletely understood. Recent research has shown that stem and progenitor cells found in the bone marrow and local vessel walls play a role in the development of arteriosclerosis by differentiating into various types of vascular cells, including endothelial cells, smooth muscle cells, fibroblasts, and inflammatory cells. This review aims to provide a comprehensive understanding of the role of stem and progenitor cells in the pathogenesis of arteriosclerosis, shedding light on the underlying mechanisms and potential therapeutic approaches for this disease.
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Affiliation(s)
- Yuesheng Zhang
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Ziyin Guan
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Hui Gong
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Zhichao Ni
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Qingzhong Xiao
- Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Xiaogang Guo
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Qingbo Xu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
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7
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Cai J, Deng Y, Min Z, Li C, Zhao Z, Jing D. Deciphering the dynamics: Exploring the impact of mechanical forces on histone acetylation. FASEB J 2024; 38:e23849. [PMID: 39096133 DOI: 10.1096/fj.202400907rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/01/2024] [Accepted: 07/21/2024] [Indexed: 08/04/2024]
Abstract
Living cells navigate a complex landscape of mechanical cues that influence their behavior and fate, originating from both internal and external sources. At the molecular level, the translation of these physical stimuli into cellular responses relies on the intricate coordination of mechanosensors and transducers, ultimately impacting chromatin compaction and gene expression. Notably, epigenetic modifications on histone tails govern the accessibility of gene-regulatory sites, thereby regulating gene expression. Among these modifications, histone acetylation emerges as particularly responsive to the mechanical microenvironment, exerting significant control over cellular activities. However, the precise role of histone acetylation in mechanosensing and transduction remains elusive due to the complexity of the acetylation network. To address this gap, our aim is to systematically explore the key regulators of histone acetylation and their multifaceted roles in response to biomechanical stimuli. In this review, we initially introduce the ubiquitous force experienced by cells and then explore the dynamic alterations in histone acetylation and its associated co-factors, including HDACs, HATs, and acetyl-CoA, in response to these biomechanical cues. Furthermore, we delve into the intricate interactions between histone acetylation and mechanosensors/mechanotransducers, offering a comprehensive analysis. Ultimately, this review aims to provide a holistic understanding of the nuanced interplay between histone acetylation and mechanical forces within an academic framework.
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Affiliation(s)
- Jingyi Cai
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yudi Deng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ziyang Min
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chaoyuan Li
- Department of Implantology, School and Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dian Jing
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
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8
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Fu B, Shen J, Zou X, Sun N, Zhang Z, Liu Z, Zeng C, Liu H, Huang W. Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. Bone Res 2024; 12:32. [PMID: 38789434 PMCID: PMC11126418 DOI: 10.1038/s41413-024-00333-9] [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: 12/06/2023] [Revised: 02/13/2024] [Accepted: 04/01/2024] [Indexed: 05/26/2024] Open
Abstract
Extracellular matrix (ECM) stiffening is a typical characteristic of cartilage aging, which is a quintessential feature of knee osteoarthritis (KOA). However, little is known about how ECM stiffening affects chondrocytes and other molecules downstream. This study mimicked the physiological and pathological stiffness of human cartilage using polydimethylsiloxane (PDMS) substrates. It demonstrated that epigenetic Parkin regulation by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiffness matrix affected chondrocyte physiology. We found that ECM stiffening accelerated cultured chondrocyte senescence in vitro, while the stiffness ECM downregulated HDAC3, prompting Parkin acetylation to activate excessive mitophagy and accelerating chondrocyte senescence and osteoarthritis (OA) in mice. Contrarily, intra-articular injection with an HDAC3-expressing adeno-associated virus restored the young phenotype of the aged chondrocytes stimulated by ECM stiffening and alleviated OA in mice. The findings indicated that changes in the mechanical ECM properties initiated pathogenic mechanotransduction signals, promoted the Parkin acetylation and hyperactivated mitophagy, and damaged chondrocyte health. These results may provide new insights into chondrocyte regulation by the mechanical properties of ECM, suggesting that the modification of the physical ECM properties may be a potential OA treatment strategy.
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Affiliation(s)
- Bowen Fu
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510145, Guangdong, China
- Department of Foot and Ankle Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China
| | - Jianlin Shen
- Department of Orthopedics, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
- Central Laboratory, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Xuenong Zou
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Nian Sun
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510145, Guangdong, China
- Department of Foot and Ankle Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China
| | - Ze Zhang
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Guangzhou Blood Center, Guangzhou, 510095, Guangdong, China
| | - Zengping Liu
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Guangzhou Blood Center, Guangzhou, 510095, Guangdong, China
| | - Canjun Zeng
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510145, Guangdong, China
- Department of Foot and Ankle Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China
| | - Huan Liu
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Wenhua Huang
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China.
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510145, Guangdong, China.
- Department of Foot and Ankle Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, Guangdong, China.
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Swiatlowska P, Iskratsch T. Cardiovascular Mechano-Epigenetics: Force-Dependent Regulation of Histone Modifications and Gene Regulation. Cardiovasc Drugs Ther 2024; 38:215-222. [PMID: 36653625 PMCID: PMC10959834 DOI: 10.1007/s10557-022-07422-z] [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] [Accepted: 12/28/2022] [Indexed: 01/19/2023]
Abstract
The local mechanical microenvironment impacts on the cell behavior. In the cardiovascular system, cells in both the heart and the vessels are exposed to continuous blood flow, blood pressure, stretching forces, and changing extracellular matrix stiffness. The force-induced signals travel all the way to the nucleus regulating epigenetic changes such as chromatin dynamics and gene expression. Mechanical cues are needed at the very early stage for a faultless embryological development, while later in life, aberrant mechanical signaling can lead to a range of pathologies, including diverse cardiovascular diseases. Hence, an investigation of force-generated epigenetic alteration at different time scales is needed to understand fully the phenotypic changes in disease onset and progression. That being so, cardiovascular mechano-epigenetics emerges as an attractive field of study. Given the rapid advances in this emergent field of research, this short review aims to provide an analysis of the state of knowledge of force-induced epigenetic changes in the cardiovascular field.
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Affiliation(s)
- Pamela Swiatlowska
- School of Engineering and Materials Science, Queen Mary University of London, London, UK
| | - Thomas Iskratsch
- School of Engineering and Materials Science, Queen Mary University of London, London, UK.
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10
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Fraile-Martinez O, De Leon-Oliva D, Boaru DL, De Castro-Martinez P, Garcia-Montero C, Barrena-Blázquez S, García-García J, García-Honduvilla N, Alvarez-Mon M, Lopez-Gonzalez L, Diaz-Pedrero R, Guijarro LG, Ortega MA. Connecting epigenetics and inflammation in vascular senescence: state of the art, biomarkers and senotherapeutics. Front Genet 2024; 15:1345459. [PMID: 38469117 PMCID: PMC10925776 DOI: 10.3389/fgene.2024.1345459] [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: 11/27/2023] [Accepted: 02/15/2024] [Indexed: 03/13/2024] Open
Abstract
Vascular diseases pose major health challenges, and understanding their underlying molecular mechanisms is essential to advance therapeutic interventions. Cellular senescence, a hallmark of aging, is a cellular state characterized by cell-cycle arrest, a senescence-associated secretory phenotype macromolecular damage, and metabolic dysregulation. Vascular senescence has been demonstrated to play a key role in different vascular diseases, such as atherosclerosis, peripheral arterial disease, hypertension, stroke, diabetes, chronic venous disease, and venous ulcers. Even though cellular senescence was first described in 1961, significant gaps persist in comprehending the epigenetic mechanisms driving vascular senescence and its subsequent inflammatory response. Through a comprehensive analysis, we aim to elucidate these knowledge gaps by exploring the network of epigenetic alterations that contribute to vascular senescence. In addition, we describe the consequent inflammatory cascades triggered by these epigenetic modifications. Finally, we explore translational applications involving biomarkers of vascular senescence and the emerging field of senotherapy targeting this biological process.
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Affiliation(s)
- Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Diego De Leon-Oliva
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Patricia De Castro-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Silvestra Barrena-Blázquez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Joaquin García-García
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, Alcala deHenares, Spain
| | - Laura Lopez-Gonzalez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
| | - Raul Diaz-Pedrero
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Department of General and Digestive Surgery, General and Digestive Surgery, Príncipe de Asturias Universitary Hospital, Alcala deHenares, Spain
| | - Luis G. Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
- Department of General and Digestive Surgery, General and Digestive Surgery, Príncipe de Asturias Universitary Hospital, Alcala deHenares, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, Alcala deHenares, Spain
| | - Miguel A. Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala deHenares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, Alcala deHenares, Spain
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11
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Jun JH, Kim JS, Palomera LF, Jo DG. Dysregulation of histone deacetylases in ocular diseases. Arch Pharm Res 2024; 47:20-39. [PMID: 38151648 DOI: 10.1007/s12272-023-01482-x] [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: 06/15/2023] [Accepted: 12/20/2023] [Indexed: 12/29/2023]
Abstract
Ocular diseases are a growing global concern and have a significant impact on the quality of life. Cataracts, glaucoma, age-related macular degeneration, and diabetic retinopathy are the most prevalent ocular diseases. Their prevalence and the global market size are also increasing. However, the available pharmacotherapy is currently limited. These diseases share common pathophysiological features, including neovascularization, inflammation, and/or neurodegeneration. Histone deacetylases (HDACs) are a class of enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins. HDACs are crucial for regulating various cellular processes, such as gene expression, protein stability, localization, and function. They have also been studied in various research fields, including cancer, inflammatory diseases, neurological disorders, and vascular diseases. Our study aimed to investigate the relationship between HDACs and ocular diseases, to identify a new strategy for pharmacotherapy. This review article explores the role of HDACs in ocular diseases, specifically focusing on diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity, as well as optic nerve disorders, such as glaucoma and optic neuropathy. Additionally, we explore the interplay between HDACs and key regulators of fibrosis and angiogenesis, such as TGF-β and VEGF, highlighting the potential of targeting HDAC as novel therapeutic strategies for ocular diseases.
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Affiliation(s)
- Jae Hyun Jun
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea
- Department of Pharmacology, CKD Research Institute, Chong Kun Dang Pharmaceutical Co., Yongin, 16995, Korea
| | - Jun-Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea
| | - Leon F Palomera
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea.
- Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Korea.
- Biomedical Institute for Convergence, Sungkyunkwan University, Suwon, 16419, Korea.
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12
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Beljkas M, Ilic A, Cebzan A, Radovic B, Djokovic N, Ruzic D, Nikolic K, Oljacic S. Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer. Pharmaceutics 2023; 15:2581. [PMID: 38004560 PMCID: PMC10674519 DOI: 10.3390/pharmaceutics15112581] [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: 09/30/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.
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Affiliation(s)
| | | | | | | | | | | | - Katarina Nikolic
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (M.B.); (A.I.); (A.C.); (B.R.); (N.D.); (D.R.)
| | - Slavica Oljacic
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (M.B.); (A.I.); (A.C.); (B.R.); (N.D.); (D.R.)
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13
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Yang M, Zhou X, Pearce SW, Yang Z, Chen Q, Niu K, Liu C, Luo J, Li D, Shao Y, Zhang C, Chen D, Wu Q, Cutillas PR, Zhao L, Xiao Q, Zhang L. Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice. Arterioscler Thromb Vasc Biol 2023; 43:1900-1920. [PMID: 37589142 PMCID: PMC10521802 DOI: 10.1161/atvbaha.123.319281] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved. METHODS β-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD. RESULTS NE aortic gene expression and plasma activity was significantly increased during β-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents β-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to MECP2 and LTA4H gene promoters, respectively. Finally, adeno-associated virus-2-mediated Tbl1x gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation. CONCLUSIONS We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients.
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Affiliation(s)
- Mei Yang
- Department of Cardiology, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China (M.Y., Q.C., D.L., L. Zhang)
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
| | - Xinmiao Zhou
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
- Department of Respiratory and Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China (X.Z.)
| | - Stuart W.A. Pearce
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
| | - Zhisheng Yang
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
| | - Qishan Chen
- Department of Cardiology, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China (M.Y., Q.C., D.L., L. Zhang)
| | - Kaiyuan Niu
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
| | - Chenxin Liu
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
| | - Jun Luo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.S., C.Z., D.C., Q.W.)
| | - Dan Li
- Department of Cardiology, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China (M.Y., Q.C., D.L., L. Zhang)
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, China (D.L., L. Zhao)
| | - Yue Shao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.S., C.Z., D.C., Q.W.)
| | - Cheng Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.S., C.Z., D.C., Q.W.)
| | - Dan Chen
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.S., C.Z., D.C., Q.W.)
| | - Qingchen Wu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.S., C.Z., D.C., Q.W.)
| | - Pedro R. Cutillas
- Faculty of Medicine and Dentistry, Centre for Haemato-Oncology, Barts Cancer Institute (P.R.C.), Queen Mary University of London, United Kingdom
| | - Lin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, China (D.L., L. Zhao)
| | - Qingzhong Xiao
- Faculty of Medicine and Dentistry, William Harvey Research Institute (M.Y., X.Z., S.W.A.P., Z.Y., K.N., C.L., Q.X.), Queen Mary University of London, United Kingdom
- Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, China (Q.X.)
| | - Li Zhang
- Department of Cardiology, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China (M.Y., Q.C., D.L., L. Zhang)
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14
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Targeted Inhibition of Matrix Metalloproteinase-8 Prevents Aortic Dissection in a Murine Model. Cells 2022; 11:cells11203218. [PMID: 36291087 PMCID: PMC9600539 DOI: 10.3390/cells11203218] [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: 08/16/2022] [Revised: 09/30/2022] [Accepted: 10/11/2022] [Indexed: 11/16/2022] Open
Abstract
Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.
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15
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Jiang M, Ding H, Huang Y, Wang L. Shear Stress and Metabolic Disorders-Two Sides of the Same Plaque. Antioxid Redox Signal 2022; 37:820-841. [PMID: 34148374 DOI: 10.1089/ars.2021.0126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Significance: Shear stress and metabolic disorder are the two sides of the same atherosclerotic coin. Atherosclerotic lesions are prone to develop at branches and curvatures of arteries, which are exposed to oscillatory and low shear stress exerted by blood flow. Meanwhile, metabolic disorders are pivotal contributors to the formation and advancement of atherosclerotic plaques. Recent Advances: Accumulated evidence has provided insight into the impact and mechanisms of biomechanical forces and metabolic disorder on atherogenesis, in association with mechanotransduction, epigenetic regulation, and so on. Moreover, recent studies have shed light on the cross talk between the two drivers of atherosclerosis. Critical Issues: There are extensive cross talk and interactions between shear stress and metabolic disorder during the pathogenesis of atherosclerosis. The communications may amplify the proatherogenic effects through increasing oxidative stress and inflammation. Nonetheless, the precise mechanisms underlying such interactions remain to be fully elucidated as the cross talk network is considerably complex. Future Directions: A better understanding of the cross talk network may confer benefits for a more comprehensive clinical management of atherosclerosis. Critical mediators of the cross talk may serve as promising therapeutic targets for atherosclerotic vascular diseases, as they can inhibit effects from both sides of the plaque. Hence, further in-depth investigations with advanced omics approaches are required to develop novel and effective therapeutic strategies against atherosclerosis. Antioxid. Redox Signal. 37, 820-841.
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Affiliation(s)
- Minchun Jiang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Huanyu Ding
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yu Huang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Li Wang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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16
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Wang H, Xing M, Deng W, Qian M, Wang F, Wang K, Midgley AC, Zhao Q. Anti-Sca-1 antibody-functionalized vascular grafts improve vascular regeneration via selective capture of endogenous vascular stem/progenitor cells. Bioact Mater 2022; 16:433-450. [PMID: 35415291 PMCID: PMC8965769 DOI: 10.1016/j.bioactmat.2022.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/18/2022] [Accepted: 03/04/2022] [Indexed: 12/17/2022] Open
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17
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Liu C, Niu K, Xiao Q. Updated perspectives on vascular cell specification and pluripotent stem cell-derived vascular organoids for studying vasculopathies. Cardiovasc Res 2022; 118:97-114. [PMID: 33135070 PMCID: PMC8752356 DOI: 10.1093/cvr/cvaa313] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/15/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023] Open
Abstract
Vasculopathy is a pathological process occurring in the blood vessel wall, which could affect the haemostasis and physiological functions of all the vital tissues/organs and is one of the main underlying causes for a variety of human diseases including cardiovascular diseases. Current pharmacological interventions aiming to either delay or stop progression of vasculopathies are suboptimal, thus searching novel, targeted, risk-reducing therapeutic agents, or vascular grafts with full regenerative potential for patients with vascular abnormalities are urgently needed. Since first reported, pluripotent stem cells (PSCs), particularly human-induced PSCs, have open new avenue in all research disciplines including cardiovascular regenerative medicine and disease remodelling. Assisting with recent technological breakthroughs in tissue engineering, in vitro construction of tissue organoid made a tremendous stride in the past decade. In this review, we provide an update of the main signal pathways involved in vascular cell differentiation from human PSCs and an extensive overview of PSC-derived tissue organoids, highlighting the most recent discoveries in the field of blood vessel organoids as well as vascularization of other complex tissue organoids, with the aim of discussing the key cellular and molecular players in generating vascular organoids.
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MESH Headings
- Blood Vessels/metabolism
- Blood Vessels/pathology
- Blood Vessels/physiopathology
- Cell Culture Techniques
- Cell Differentiation
- Cell Lineage
- Cells, Cultured
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Humans
- Induced Pluripotent Stem Cells/metabolism
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Neovascularization, Pathologic
- Neovascularization, Physiologic
- Organoids
- Phenotype
- Signal Transduction
- Vascular Diseases/metabolism
- Vascular Diseases/pathology
- Vascular Diseases/physiopathology
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Affiliation(s)
- Chenxin Liu
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Heart Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Kaiyuan Niu
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Heart Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Qingzhong Xiao
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Heart Centre, Charterhouse Square, London EC1M 6BQ, UK
- Key Laboratory of Cardiovascular Diseases at The Second Affiliated Hospital
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou, Guangdong 511436, China
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18
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Wang T, Zhou J, Zhang X, Wu Y, Jin K, Wang Y, Xu R, Yang G, Li W, Jiao L. X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis. Aging Dis 2022; 14:350-369. [PMID: 37008067 PMCID: PMC10017146 DOI: 10.14336/ad.2022.0824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022] Open
Abstract
Atherosclerosis (AS), the formation of fibrofatty lesions in the vessel wall, is the primary cause of heart disease and stroke and is closely associated with aging. Disrupted metabolic homeostasis is a primary feature of AS and leads to endoplasmic reticulum (ER) stress, which is an abnormal accumulation of unfolded proteins. By orchestrating signaling cascades of the unfolded protein response (UPR), ER stress functions as a double-edged sword in AS, where adaptive UPR triggers synthetic metabolic processes to restore homeostasis, whereas the maladaptive response programs the cell to the apoptotic pathway. However, little is known regarding their precise coordination. Herein, an advanced understanding of the role of UPR in the pathological process of AS is reviewed. In particular, we focused on a critical mediator of the UPR, X-box binding protein 1 (XBP1), and its important role in balancing adaptive and maladaptive responses. The XBP1 mRNA is processed from the unspliced isoform (XBP1u) to the spliced isoform of XBP1 (XBP1s). Compared with XBP1u, XBP1s predominantly functions downstream of inositol-requiring enzyme-1α (IRE1α) and transcript genes involved in protein quality control, inflammation, lipid metabolism, carbohydrate metabolism, and calcification, which are critical for the pathogenesis of AS. Thus, the IRE1α/XBP1 axis is a promising pharmaceutical candidate against AS.
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Affiliation(s)
- Tao Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
- China International Neuroscience Institute (China-INI), Beijing, China.
| | - Jia Zhou
- Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
| | - Xiao Zhang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
- China International Neuroscience Institute (China-INI), Beijing, China.
| | - Yujie Wu
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
| | - Kehan Jin
- Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
| | - Yilin Wang
- Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Ran Xu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
- China International Neuroscience Institute (China-INI), Beijing, China.
| | - Ge Yang
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
- School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China.
- Correspondence should be addressed to: Dr. Ge Yang, Chinese Academy of Sciences, Beijing, China. , Dr. Wenjing Li, Chinese Academy of Sciences, Beijing, China. ; Dr. Liqun Jiao, Xuanwu Hospital, Capital Medical University, Beijing, China. .
| | - Wenjing Li
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
- School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China.
- Correspondence should be addressed to: Dr. Ge Yang, Chinese Academy of Sciences, Beijing, China. , Dr. Wenjing Li, Chinese Academy of Sciences, Beijing, China. ; Dr. Liqun Jiao, Xuanwu Hospital, Capital Medical University, Beijing, China. .
| | - Liqun Jiao
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
- China International Neuroscience Institute (China-INI), Beijing, China.
- Department of Interventional Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China.
- Correspondence should be addressed to: Dr. Ge Yang, Chinese Academy of Sciences, Beijing, China. , Dr. Wenjing Li, Chinese Academy of Sciences, Beijing, China. ; Dr. Liqun Jiao, Xuanwu Hospital, Capital Medical University, Beijing, China. .
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Jiang LP, Yu XH, Chen JZ, Hu M, Zhang YK, Lin HL, Tang WY, He PP, Ouyang XP. Histone Deacetylase 3: A Potential Therapeutic Target for Atherosclerosis. Aging Dis 2022; 13:773-786. [PMID: 35656103 PMCID: PMC9116907 DOI: 10.14336/ad.2021.1116] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/16/2021] [Indexed: 11/17/2022] Open
Abstract
Atherosclerosis, the pathological basis of most cardiovascular disease, is characterized by plaque formation in the intima. Secondary lesions include intraplaque hemorrhage, plaque rupture, and local thrombosis. Vascular endothelial function impairment and smooth muscle cell migration lead to vascular dysfunction, which is conducive to the formation of macrophage-derived foam cells and aggravates inflammatory response and lipid accumulation that cause atherosclerosis. Histone deacetylase (HDAC) is an epigenetic modifying enzyme closely related to chromatin structure and gene transcriptional regulation. Emerging studies have demonstrated that the Class I member HDAC3 of the HDAC super family has cell-specific functions in atherosclerosis, including 1) maintenance of endothelial integrity and functions, 2) regulation of vascular smooth muscle cell proliferation and migration, 3) modulation of macrophage phenotype, and 4) influence on foam cell formation. Although several studies have shown that HDAC3 may be a promising therapeutic target, only a few HDAC3-selective inhibitors have been thoroughly researched and reported. Here, we specifically summarize the impact of HDAC3 and its inhibitors on vascular function, inflammation, lipid accumulation, and plaque stability in the development of atherosclerosis with the hopes of opening up new opportunities for the treatment of cardiovascular diseases.
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Affiliation(s)
- Li-Ping Jiang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, Haikou, China.
| | - Jin-Zhi Chen
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Mi Hu
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Yang-Kai Zhang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Hui-Ling Lin
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Wan-Ying Tang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Ping-Ping He
- School of Nursing, University of South China, Hunan, China
- Correspondence should be addressed to: Dr. Ping-Ping He, School of Nursing, University of South China, Hunan, China. and Dr. Xin-Ping Ouyang, Department of Physiology, University of South China, Hunan, China. .
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
- Correspondence should be addressed to: Dr. Ping-Ping He, School of Nursing, University of South China, Hunan, China. and Dr. Xin-Ping Ouyang, Department of Physiology, University of South China, Hunan, China. .
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20
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Wang X, Wang R, Jiang L, Xu Q, Guo X. Endothelial repair by stem and progenitor cells. J Mol Cell Cardiol 2021; 163:133-146. [PMID: 34743936 DOI: 10.1016/j.yjmcc.2021.10.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 12/19/2022]
Abstract
The integrity of the endothelial barrier is required to maintain vascular homeostasis and fluid balance between the circulatory system and surrounding tissues and to prevent the development of vascular disease. However, the origin of the newly developed endothelial cells is still controversial. Stem and progenitor cells have the potential to differentiate into endothelial cell lines and stimulate vascular regeneration in a paracrine/autocrine fashion. The one source of new endothelial cells was believed to come from the bone marrow, which was challenged by the recent findings. By administration of new techniques, including genetic cell lineage tracing and single cell RNA sequencing, more solid data were obtained that support the concept of stem/progenitor cells for regenerating damaged endothelium. Specifically, it was found that tissue resident endothelial progenitors located in the vessel wall were crucial for endothelial repair. In this review, we summarized the latest advances in stem and progenitor cell research in endothelial regeneration through findings from animal models and discussed clinical data to indicate the future direction of stem cell therapy.
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Affiliation(s)
- Xuyang Wang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ruilin Wang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liujun Jiang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Xiaogang Guo
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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21
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Huang Y, Qian JY, Cheng H, Li XM. Effects of shear stress on differentiation of stem cells into endothelial cells. World J Stem Cells 2021; 13:894-913. [PMID: 34367483 PMCID: PMC8316872 DOI: 10.4252/wjsc.v13.i7.894] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/20/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell transplantation is an appealing potential therapy for vascular diseases and an indispensable key step in vascular tissue engineering. Substantial effort has been made to differentiate stem cells toward vascular cell phenotypes, including endothelial cells (ECs) and smooth muscle cells. The microenvironment of vascular cells not only contains biochemical factors that influence differentiation but also exerts hemodynamic forces, such as shear stress and cyclic strain. More recently, studies have shown that shear stress can influence the differentiation of stem cells toward ECs. A deep understanding of the responses and underlying mechanisms involved in this process is essential for clinical translation. This review highlights current data supporting the role of shear stress in stem cell differentiation into ECs. Potential mechanisms and signaling cascades for transducing shear stress into a biological signal are proposed. Further study of stem cell responses to shear stress will be necessary to apply stem cells for pharmacological applications and cardiovascular implants in the realm of regenerative medicine.
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Affiliation(s)
- Yan Huang
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Jia-Yi Qian
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Hong Cheng
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Xiao-Ming Li
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China.
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Huang S, Chen G, Sun J, Chen Y, Wang N, Dong Y, Shen E, Hu Z, Gong W, Jin L, Cong W. Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2. Cell Commun Signal 2021; 19:35. [PMID: 33736642 PMCID: PMC7977318 DOI: 10.1186/s12964-020-00681-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 11/02/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The mechanism underlying endothelial dysfunction leading to cardiovascular disease in type 2 diabetes mellitus (T2DM) remains unclear. Here, we show that inhibition of histone deacetylase 3 (HDAC3) reduced inflammation and oxidative stress by regulating nuclear factor-E2-related factor 2 (Nrf2), which mediates the expression of anti-inflammatory- and pro-survival-related genes in the vascular endothelium, thereby improving endothelial function. METHODS Nrf2 knockout (Nrf2 KO) C57BL/6 background mice, diabetic db/db mice, and control db/m mice were used to investigate the relationship between HDAC3 and Nrf2 in the endothelium in vivo. Human umbilical vein endothelial cells (HUVECs) cultured under high glucose-palmitic acid (HG-PA) conditions were used to explore the role of Kelch-like ECH-associated protein 1 (Keap1) -Nrf2-NAPDH oxidase 4 (Nox4) redox signaling in the vascular endothelium in vitro. Activity assays, immunofluorescence, western blotting, qRT-PCR, and immunoprecipitation assays were used to examine the effect of HDAC3 inhibition on inflammation, reactive oxygen species (ROS) production, and endothelial impairment, as well as the activity of Nrf2-related molecules. RESULTS HDAC3 activity, but not its expression, was increased in db/db mice. This resulted in de-endothelialization and increased oxidative stress and pro-inflammatory marker expression in cells treated with the HDAC3 inhibitor RGFP966, which activated Nrf2 signaling. HDAC3 silencing decreased ROS production, inflammation, and damage-associated tube formation in HG-PA-treated HUVECs. The underlying mechanism involved the Keap1-Nrf2-Nox4 signaling pathway. CONCLUSION The results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM. Video Abstract.
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Affiliation(s)
- Shuai Huang
- Zhejiang Provincial Key Laboratory of Interventional Pulmonology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Gen Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Jia Sun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Yunjie Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Nan Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Yetong Dong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Enzhao Shen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Zhicheng Hu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Wenjie Gong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
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Yang X, Yang Y, Guo J, Meng Y, Li M, Yang P, Liu X, Aung LHH, Yu T, Li Y. Targeting the epigenome in in-stent restenosis: from mechanisms to therapy. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:1136-1160. [PMID: 33664994 PMCID: PMC7896131 DOI: 10.1016/j.omtn.2021.01.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Coronary artery disease (CAD) is one of the most common causes of death worldwide. The introduction of percutaneous revascularization has revolutionized the therapy of patients with CAD. Despite the advent of drug-eluting stents, restenosis remains the main challenge in treating patients with CAD. In-stent restenosis (ISR) indicates the reduction in lumen diameter after percutaneous coronary intervention, in which the vessel's lumen re-narrowing is attributed to the aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) and dysregulation of endothelial cells (ECs). Increasing evidence has demonstrated that epigenetics is involved in the occurrence and progression of ISR. In this review, we provide the latest and comprehensive analysis of three separate but related epigenetic mechanisms regulating ISR, namely, DNA methylation, histone modification, and non-coding RNAs. Initially, we discuss the mechanism of restenosis. Furthermore, we discuss the biological mechanism underlying the diverse epigenetic modifications modulating gene expression and functions of VSMCs, as well as ECs in ISR. Finally, we discuss potential therapeutic targets of the small molecule inhibitors of cardiovascular epigenetic factors. A more detailed understanding of epigenetic regulation is essential for elucidating this complex biological process, which will assist in developing and improving ISR therapy.
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Affiliation(s)
- Xi Yang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, No. 308 Ningxia Road, Qingdao 266071, People’s Republic of China
| | - Junjie Guo
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
| | - Yuanyuan Meng
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, People’s Republic of China
| | - Min Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People’s Republic of China
| | - Panyu Yang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, People’s Republic of China
| | - Xin Liu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
| | - Lynn Htet Htet Aung
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People’s Republic of China
| | - Tao Yu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, People’s Republic of China
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People’s Republic of China
| | - Yonghong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
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24
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Domínguez-Bautista JA, Acevo-Rodríguez PS, Castro-Obregón S. Programmed Cell Senescence in the Mouse Developing Spinal Cord and Notochord. Front Cell Dev Biol 2021; 9:587096. [PMID: 33575260 PMCID: PMC7870793 DOI: 10.3389/fcell.2021.587096] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 01/05/2021] [Indexed: 01/10/2023] Open
Abstract
Programmed cell senescence is a cellular process that seems to contribute to embryo development, in addition to cell proliferation, migration, differentiation and programmed cell death, and has been observed in evolutionary distant organisms such as mammals, amphibians, birds and fish. Programmed cell senescence is a phenotype similar to stress-induced cellular senescence, characterized by the expression of the cell cycle inhibitors p21CIP1/WAF and p16INK4A, increased activity of a lysosomal enzyme with beta-galactosidase activity (coined senescence-associated beta-galactosidase) and secretion of growth factors, interleukins, chemokines, metalloproteases, etc., collectively known as a senescent-associated secretory phenotype that instructs surrounding tissue. How wide is the distribution of programmed cell senescence during mouse development and its specific mechanisms to shape the embryo are still poorly understood. Here, we investigated whether markers of programmed cell senescence are found in the developing mouse spinal cord and notochord. We found discrete areas and developmental windows with high senescence-associated beta galactosidase in both spinal cord and notochord, which was reduced in mice embryos developed ex-utero in the presence of the senolytic ABT-263. Expression of p21CIP1/WAF was documented in epithelial cells of the spinal cord and the notochord, while p16INK4A was observed in motoneurons. Treatment with the senolytic ABT-263 decreased the number of motoneurons, supporting their senescent phenotype. Our data suggest that a subpopulation of motoneurons in the developing spinal cord, as well as some notochord cells undergo programmed cell senescence.
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Affiliation(s)
| | | | - Susana Castro-Obregón
- División de Neurociencias, Instituto de Fisiología Celular, UNAM, Mexico City, Mexico
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25
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Angbohang A, Huang L, Li Y, Zhao Y, Gong Y, Fu Y, Mao C, Morales J, Luo P, Ehteramyan M, Gao Y, Margariti A, Gu W, Zhang M, Smith A, Shah AM, Li T, Kong W, Zeng L. X-box binding protein 1-mediated COL4A1s secretion regulates communication between vascular smooth muscle and stem/progenitor cells. J Biol Chem 2021; 296:100541. [PMID: 33722606 PMCID: PMC8063738 DOI: 10.1016/j.jbc.2021.100541] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 11/23/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) contribute to the deposition of extracellular matrix proteins (ECMs), including Type IV collagen, in the vessel wall. ECMs coordinate communication among different cell types, but mechanisms underlying this communication remain unclear. Our previous studies have demonstrated that X-box binding protein 1 (XBP1) is activated and contributes to VSMC phenotypic transition in response to vascular injury. In this study, we investigated the participation of XBP1 in the communication between VSMCs and vascular progenitor cells (VPCs). Immunofluorescence and immunohistology staining revealed that Xbp1 gene was essential for type IV collagen alpha 1 (COL4A1) expression during mouse embryonic development and vessel wall ECM deposition and stem cell antigen 1-positive (Sca1+)-VPC recruitment in response to vascular injury. The Western blot analysis elucidated an Xbp1 gene dose-dependent effect on COL4A1 expression and that the spliced XBP1 protein (XBP1s) increased protease-mediated COL4A1 degradation as revealed by Zymography. RT-PCR analysis revealed that XBP1s in VSMCs not only upregulated COL4A1/2 transcription but also induced the occurrence of a novel transcript variant, soluble type IV collagen alpha 1 (COL4A1s), in which the front part of exon 4 is joined with the rear part of exon 42. Chromatin-immunoprecipitation, DNA/protein pulldown and in vitro transcription demonstrated that XBP1s binds to exon 4 and exon 42, directing the transcription from exon 4 to exon 42. This leads to transcription complex bypassing the internal sequences, producing a shortened COL4A1s protein that increased Sca1+-VPC migration. Taken together, these results suggest that activated VSMCs may recruit Sca1+-VPCs via XBP1s-mediated COL4A1s secretion, leading to vascular injury repair or neointima formation.
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Affiliation(s)
- Angshumonik Angbohang
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Lei Huang
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK; Department of Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, P.R. China
| | - Yi Li
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Yue Zhao
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK; Department of Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, P.R. China
| | - Yijie Gong
- The Third Central Clinical College of Tianjin Medical University, Tianjin, P.R. China
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China
| | - Chenfeng Mao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China
| | - Jose Morales
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Peiyi Luo
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Mazdak Ehteramyan
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Yingtang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, P.R. China; Tianjin Institute of Hepatobiliary Disease, the Third Affiliated Hospital of Nankai University, Tianjin, P.R. China
| | - Andriana Margariti
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Wenduo Gu
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Min Zhang
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Alberto Smith
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Ajay M Shah
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Tong Li
- Department of Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, P.R. China.
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China.
| | - Lingfang Zeng
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Science and Medicine, King's College London, London, UK.
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Mia MM, Cibi DM, Abdul Ghani SAB, Song W, Tee N, Ghosh S, Mao J, Olson EN, Singh MK. YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. PLoS Biol 2020; 18:e3000941. [PMID: 33264286 PMCID: PMC7735680 DOI: 10.1371/journal.pbio.3000941] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/14/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI. Adverse cardiac remodeling after myocardial infarction causes structural and functional changes in the heart, leading to heart failure. This study shows that the Hippo pathway influences post-injury cardiac inflammation by modulating macrophage polarization.
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Affiliation(s)
- Masum M. Mia
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore. Singapore
| | - Dasan Mary Cibi
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore. Singapore
| | | | - Weihua Song
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | - Nicole Tee
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | - Sujoy Ghosh
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore. Singapore
| | - Junhao Mao
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Eric N. Olson
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Manvendra K. Singh
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore. Singapore
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
- * E-mail:
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Chen D, Zhang C, Chen J, Yang M, Afzal TA, An W, Maguire EM, He S, Luo J, Wang X, Zhao Y, Wu Q, Xiao Q. miRNA-200c-3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts. J Pathol 2020; 253:209-224. [PMID: 33125708 PMCID: PMC7839516 DOI: 10.1002/path.5574] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 09/17/2020] [Accepted: 10/22/2020] [Indexed: 12/11/2022]
Abstract
Increasing evidence has suggested a critical role for endothelial‐to‐mesenchymal transition (EndoMT) in a variety of pathological conditions. MicroRNA‐200c‐3p (miR‐200c‐3p) has been implicated in epithelial‐to‐mesenchymal transition. However, the functional role of miR‐200c‐3p in EndoMT and neointimal hyperplasia in artery bypass grafts remains largely unknown. Here we demonstrated a critical role for miR‐200c‐3p in EndoMT. Proteomics and luciferase activity assays revealed that fermitin family member 2 (FERM2) is the functional target of miR‐200c‐3p during EndoMT. FERMT2 gene inactivation recapitulates the effect of miR‐200c‐3p overexpression on EndoMT, and the inhibitory effect of miR‐200c‐3p inhibition on EndoMT was reversed by FERMT2 knockdown. Further mechanistic studies revealed that FERM2 suppresses smooth muscle gene expression by preventing serum response factor nuclear translocation and preventing endothelial mRNA decay by interacting with Y‐box binding protein 1. In a model of aortic grafting using endothelial lineage tracing, we observed that miR‐200c‐3p expression was dramatically up‐regulated, and that EndoMT contributed to neointimal hyperplasia in grafted arteries. MiR‐200c‐3p inhibition in grafted arteries significantly up‐regulated FERM2 gene expression, thereby preventing EndoMT and reducing neointimal formation. Importantly, we found a high level of EndoMT in human femoral arteries with atherosclerotic lesions, and that miR‐200c‐3p expression was significantly increased, while FERMT2 expression levels were dramatically decreased in diseased human arteries. Collectively, we have documented an unexpected role for miR‐200c‐3p in EndoMT and neointimal hyperplasia in grafted arteries. Our findings offer a novel therapeutic opportunity for treating vascular diseases by specifically targeting the miR‐200c‐3p/FERM2 regulatory axis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Dan Chen
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Cheng Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Jiangyong Chen
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Department of Cardiothoracic Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, PR China
| | - Mei Yang
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Tayyab A Afzal
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Weiwei An
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Eithne M Maguire
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Shiping He
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jun Luo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.,Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Xiaowen Wang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Yu Zhao
- Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Qingchen Wu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Qingzhong Xiao
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Key Laboratory of Cardiovascular Diseases at The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, PR China.,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, PR China
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28
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Ding X, Xiang W, He X. IFN-I Mediates Dysfunction of Endothelial Progenitor Cells in Atherosclerosis of Systemic Lupus Erythematosus. Front Immunol 2020; 11:581385. [PMID: 33262760 PMCID: PMC7686511 DOI: 10.3389/fimmu.2020.581385] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/14/2020] [Indexed: 12/14/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system. Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality. Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells. As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE. However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined. This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.
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Affiliation(s)
- Xuewei Ding
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
- Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Xiang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, NHC Key Laboratory of Control of Tropical diseases (Hainan Medical University), Haikou, China
| | - Xiaojie He
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
- Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
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29
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Design and Characterization of a Fluidic Device for the Evaluation of SIS-Based Vascular Grafts. Processes (Basel) 2020. [DOI: 10.3390/pr8091198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Currently available small diameter vascular conduits present several long-term limitations, which has prevented their full clinical implementation. Commercially available vascular grafts show no regenerative capabilities and eventually require surgical replacement; therefore, it is of great interest to develop alternative regenerative vascular grafts (RVG). Decellularized Small Intestinal Submucosa (SIS) is an attractive material for RVG, however, the evaluation of the performance of these grafts is challenging due to the absence of devices that mimic the conditions found in vivo. Thereby, the objective of this study is to design, manufacture and validate in silico and in vitro, a novel fluidic system for the evaluation of human umbilical vein endothelial cells (HUVECs) proliferation on SIS-based RVG under dynamical conditions. Our perfusion and rotational fluidic system was designed in Autodesk Inventor 2018. In silico Computational Fluid Dynamics (CFD) validation of the system was carried out using Ansys Fluent software from ANSYS, Inc for dynamical conditions of a pulsatile pressure function measured experimentally over a rigid wall model. Mechanical and biological parameters such as flow regime, pressure gradient, wall shear stress (WSS), sterility and indirect cell viability (MTT assay) were also evaluated. Cell adhesion was confirmed by SEM imaging. The fluid flow regime within the system remains laminar. The system maintained sterility and showed low cytotoxicity levels. HUVECs were successfully cultured on SIS-based RVG under both perfusion and rotation conditions. In silico analysis agreed well with our experimental and theoretical results, and with recent in vitro and in vivo reports for WSS. The system presented is a tool for evaluating RVG and represents an alternative to develop new methods and protocols for a more comprehensive study of regenerative cardiovascular devices.
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30
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Li Q, Sun X, Tang Y, Qu Y, Zhou Y, Zhang Y. EZH2 reduction is an essential mechanoresponse for the maintenance of super-enhancer polarization against compressive stress in human periodontal ligament stem cells. Cell Death Dis 2020; 11:757. [PMID: 32934212 PMCID: PMC7493952 DOI: 10.1038/s41419-020-02963-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 08/12/2020] [Accepted: 08/27/2020] [Indexed: 12/20/2022]
Abstract
Despite the ubiquitous mechanical cues at both spatial and temporal dimensions, cell identities and functions are largely immune to the everchanging mechanical stimuli. To understand the molecular basis of this epigenetic stability, we interrogated compressive force-elicited transcriptomic changes in mesenchymal stem cells purified from human periodontal ligament (PDLSCs), and identified H3K27me3 and E2F signatures populated within upregulated and weakly downregulated genes, respectively. Consistently, expressions of several E2F family transcription factors and EZH2, as core methyltransferase for H3K27me3, decreased in response to mechanical stress, which were attributed to force-induced redistribution of RB from nucleoplasm to lamina. Importantly, although epigenomic analysis on H3K27me3 landscape only demonstrated correlating changes at one group of mechanoresponsive genes, we observed a genome-wide destabilization of super-enhancers along with aberrant EZH2 retention. These super-enhancers were tightly bounded by H3K27me3 domain on one side and exhibited attenuating H3K27ac deposition and flattening H3K27ac peaks along with compensated EZH2 expression after force exposure, analogous to increased H3K27ac entropy or decreased H3K27ac polarization. Interference of force-induced EZH2 reduction could drive actin filaments dependent spatial overlap between EZH2 and super-enhancers and functionally compromise the multipotency of PDLSC following mechanical stress. These findings together unveil a specific contribution of EZH2 reduction for the maintenance of super-enhancer stability and cell identity in mechanoresponse.
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Affiliation(s)
- Qian Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Xiwen Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yunyi Tang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yanan Qu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China.
| | - Yu Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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31
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Zhang C, Lin Y, Liu Q, He J, Xiang P, Wang D, Hu X, Chen J, Zhu W, Yu H. Growth differentiation factor 11 promotes differentiation of MSCs into endothelial-like cells for angiogenesis. J Cell Mol Med 2020; 24:8703-8717. [PMID: 32588524 PMCID: PMC7412688 DOI: 10.1111/jcmm.15502] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/20/2020] [Accepted: 05/28/2020] [Indexed: 12/11/2022] Open
Abstract
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro-angiogenic activities of MSCs, mouse bone marrow-derived MSCs were engineered to overexpress GDF11 (MSCGDF11 ) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSCGDF11 than control MSCs (MSCVector ) during differentiation. More tube formation was observed in MSCGDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSCGDF11 showed more differentiation into CD31+ endothelial-like cells and better pro-angiogenic activity as compared with MSCVector . Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular-signal-related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF-β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro-angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ-R/ERK/EIF4E pathway.
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Affiliation(s)
- Chi Zhang
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Yinuo Lin
- Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qi Liu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Junhua He
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Pingping Xiang
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Dianliang Wang
- Stem Cell and Tissue Engineering Research Laboratory, PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Xinyang Hu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Jinghai Chen
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Wei Zhu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
| | - Hong Yu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China
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32
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Nijhawan P, Behl T, Khullar G, Pal G, Kandhwal M, Goyal A. HDAC in obesity: A critical insight. ACTA ACUST UNITED AC 2020. [DOI: 10.1016/j.obmed.2020.100212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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33
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Zhao TC, Wang Z, Zhao TY. The important role of histone deacetylases in modulating vascular physiology and arteriosclerosis. Atherosclerosis 2020; 303:36-42. [PMID: 32535412 DOI: 10.1016/j.atherosclerosis.2020.04.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 04/18/2020] [Accepted: 04/29/2020] [Indexed: 12/18/2022]
Abstract
Cardiovascular diseases are the leading cause of deaths in the world. Endothelial dysfunction followed by inflammation of the vessel wall leads to atherosclerotic lesion formation that causes ischemic heart and myocardial hypertrophy, which ultimately progress into cardiac dysfunction and failure. Histone deacetylases (HDACs) have been recognized to play crucial roles in cardiovascular disease, particularly in the epigenetic regulation of gene transcription in response to a variety of stresses. The unique nature of HDAC regulation includes that HDACs form a complex co-regulatory network with other transcription factors, deacetylate histones and non-histone proteins to facilitate the regulatory mechanism of the vascular system. The selective HDAC inhibitors are considered as the most promising target in cardiovascular disease, especially for preventing cardiac hypertrophy. In this review, we discuss our present knowledge of the cellular and molecular basis of HDACs in mediating the biological function of vascular cells and related pharmacologic interventions in vascular disease.
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Affiliation(s)
- Ting C Zhao
- Department of Surgery and Plastics Surgery, Brown University, Rhode Island Hospital, Providence, RI, USA.
| | - Zhengke Wang
- Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Providence, 50 Maude Street, RI, 02908, USA
| | - Tina Y Zhao
- University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
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34
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35
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Lee DY, Chiu JJ. Atherosclerosis and flow: roles of epigenetic modulation in vascular endothelium. J Biomed Sci 2019; 26:56. [PMID: 31387590 PMCID: PMC6685237 DOI: 10.1186/s12929-019-0551-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/29/2019] [Indexed: 12/18/2022] Open
Abstract
Background Endothelial cell (EC) dysfunctions, including turnover enrichment, gap junction disruption, inflammation, and oxidation, play vital roles in the initiation of vascular disorders and atherosclerosis. Hemodynamic forces, i.e., atherprotective pulsatile (PS) and pro-atherogenic oscillatory shear stress (OS), can activate mechanotransduction to modulate EC function and dysfunction. This review summarizes current studies aiming to elucidate the roles of epigenetic factors, i.e., histone deacetylases (HDACs), non-coding RNAs, and DNA methyltransferases (DNMTs), in mechanotransduction to modulate hemodynamics-regulated EC function and dysfunction. Main body of the abstract OS enhances the expression and nuclear accumulation of class I and class II HDACs to induce EC dysfunction, i.e., proliferation, oxidation, and inflammation, whereas PS induces phosphorylation-dependent nuclear export of class II HDACs to inhibit EC dysfunction. PS induces overexpression of the class III HDAC Sirt1 to enhance nitric oxide (NO) production and prevent EC dysfunction. In addition, hemodynamic forces modulate the expression and acetylation of transcription factors, i.e., retinoic acid receptor α and krüppel-like factor-2, to transcriptionally regulate the expression of microRNAs (miRs). OS-modulated miRs, which stimulate proliferative, pro-inflammatory, and oxidative signaling, promote EC dysfunction, whereas PS-regulated miRs, which induce anti-proliferative, anti-inflammatory, and anti-oxidative signaling, inhibit EC dysfunction. PS also modulates the expression of long non-coding RNAs to influence EC function. i.e., turnover, aligmant, and migration. On the other hand, OS enhances the expression of DNMT-1 and -3a to induce EC dysfunction, i.e., proliferation, inflammation, and NO repression. Conclusion Overall, epigenetic factors play vital roles in modulating hemodynamic-directed EC dysfunction and vascular disorders, i.e., atherosclerosis. Understanding the detailed mechanisms through which epigenetic factors regulate hemodynamics-directed EC dysfunction and vascular disorders can help us to elucidate the pathogenic mechanisms of atherosclerosis and develop potential therapeutic strategies for atherosclerosis treatment.
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Affiliation(s)
- Ding-Yu Lee
- Department of Biological Science and Technology, China University of Science and Technology, Taipei, 115, Taiwan
| | - Jeng-Jiann Chiu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, 350, Taiwan. .,Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 300, Taiwan. .,Collage of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan. .,Institute of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan. .,Institute of Polymer Science and Engineering, National Taiwan University, Taipei, 106, Taiwan.
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36
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Menden H, Xia S, Mabry SM, Noel-MacDonnell J, Rajasingh J, Ye SQ, Sampath V. Histone deacetylase 6 regulates endothelial MyD88-dependent canonical TLR signaling, lung inflammation, and alveolar remodeling in the developing lung. Am J Physiol Lung Cell Mol Physiol 2019; 317:L332-L346. [PMID: 31268348 DOI: 10.1152/ajplung.00247.2018] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Lung endothelial cell (EC) immune activation during bacterial sepsis contributes to acute lung injury and bronchopulmonary dysplasia in premature infants. The epigenetic regulators of sepsis-induced endothelial immune activation, lung inflammation, and alveolar remodeling remain unclear. Herein, we examined the role of the cytoplasmic histone deacetylase, HDAC6, in regulating EC Toll-like receptor 4 (TLR4) signaling and modulating sepsis-induced lung injury in a neonatal model of sterile sepsis. In human primary microvascular endothelial cells (HPMEC), lipopolysaccharide (LPS)-induced MAPK, IKK-β, and p65 phosphorylation as well as inflammatory cytokine expression were exaggerated with the HDAC6 inhibitor tubastatin A, and by dominant-negative HDAC6 with a mutated catalytic domain 2. Expression of HDAC6 wild-type protein suppressed LPS-induced myeloid differentiation primary response 88 (MyD88) acetylation, p65 (Lys310) acetylation, MyD88/TNF receptor-associated factor 6 (TRAF6) coimmunoprecipitation, and proinflammatory TLR4 signaling in HPMEC. In a neonatal mouse model of sepsis, the HDAC6 inhibitor tubastatin A amplified lung EC TLR4 signaling and vascular permeability. HDAC6 inhibition augmented LPS-induced MyD88 acetylation, MyD88/TRAF6 binding, p65 acetylation, canonical TLR4 signaling, and inflammation in the developing lung. Sepsis-induced decreases in the fibroblast growth factors FGF2 and FGF7 and increase in matrix metalloproteinase-9 were worsened with HDAC6 inhibition, while elastin expression was equally suppressed. Exaggerated sepsis-induced acute lung inflammation observed with HDAC6 inhibition worsened alveolar simplification evidenced by increases in mean linear intercepts and decreased radial alveolar counts. Our studies reveal that HDAC6 is a constitutive negative regulator of cytoplasmic TLR4 signaling in EC and the developing lung. The therapeutic efficacy of augmenting HDAC6 activity in neonatal sepsis to prevent lung injury needs to be evaluated.
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Affiliation(s)
- Heather Menden
- Division of Neonatology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri
| | - Sheng Xia
- Division of Neonatology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri
| | - Sherry M Mabry
- Division of Neonatology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri
| | - Janelle Noel-MacDonnell
- Division of Health Services and Outcomes Research, Children's Mercy Hospital, Kansas City, Missouri
| | - Johnson Rajasingh
- Department of Cardiovascular Medicine, Kansas University Medical Center, Kansas City, Missouri
| | - Shui Qing Ye
- Department of Biomedical and Health Informatics, University of Missouri at Kansas City, Kansas City, Missouri
| | - Venkatesh Sampath
- Division of Neonatology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri
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37
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Xu S, Kamato D, Little PJ, Nakagawa S, Pelisek J, Jin ZG. Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics. Pharmacol Ther 2019; 196:15-43. [PMID: 30439455 PMCID: PMC6450782 DOI: 10.1016/j.pharmthera.2018.11.003] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics.
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Affiliation(s)
- Suowen Xu
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | - Danielle Kamato
- School of Pharmacy, The University of Queensland, Wooloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou 510520, China
| | - Peter J Little
- School of Pharmacy, The University of Queensland, Wooloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou 510520, China
| | - Shinichi Nakagawa
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Jaroslav Pelisek
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Germany
| | - Zheng Gen Jin
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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38
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Gogiraju R, Bochenek ML, Schäfer K. Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure. Front Cardiovasc Med 2019; 6:20. [PMID: 30895179 PMCID: PMC6415587 DOI: 10.3389/fcvm.2019.00020] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/14/2019] [Indexed: 12/30/2022] Open
Abstract
Endothelial cells are, by number, one of the most abundant cell types in the heart and active players in cardiac physiology and pathology. Coronary angiogenesis plays a vital role in maintaining cardiac vascularization and perfusion during physiological and pathological hypertrophy. On the other hand, a reduction in cardiac capillary density with subsequent tissue hypoxia, cell death and interstitial fibrosis contributes to the development of contractile dysfunction and heart failure, as suggested by clinical as well as experimental evidence. Although the molecular causes underlying the inadequate (with respect to the increased oxygen and energy demands of the hypertrophied cardiomyocyte) cardiac vascularization developing during pathological hypertrophy are incompletely understood. Research efforts over the past years have discovered interesting mediators and potential candidates involved in this process. In this review article, we will focus on the vascular changes occurring during cardiac hypertrophy and the transition toward heart failure both in human disease and preclinical models. We will summarize recent findings in transgenic mice and experimental models of cardiac hypertrophy on factors expressed and released from cardiomyocytes, pericytes and inflammatory cells involved in the paracrine (dys)regulation of cardiac angiogenesis. Moreover, we will discuss major signaling events of critical angiogenic ligands in endothelial cells and their possible disturbance by hypoxia or oxidative stress. In this regard, we will particularly highlight findings on negative regulators of angiogenesis, including protein tyrosine phosphatase-1B and tumor suppressor p53, and how they link signaling involved in cell growth and metabolic control to cardiac angiogenesis. Besides endothelial cell death, phenotypic conversion and acquisition of myofibroblast-like characteristics may also contribute to the development of cardiac fibrosis, the structural correlate of cardiac dysfunction. Factors secreted by (dysfunctional) endothelial cells and their effects on cardiomyocytes including hypertrophy, contractility and fibrosis, close the vicious circle of reciprocal cell-cell interactions within the heart during pathological hypertrophy remodeling.
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Affiliation(s)
- Rajinikanth Gogiraju
- Center for Cardiology, Cardiology I, Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, Germany
| | - Magdalena L Bochenek
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, Germany
| | - Katrin Schäfer
- Center for Cardiology, Cardiology I, Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, Germany
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Micheu MM, Scarlatescu AI, Scafa-Udriste A, Dorobantu M. The Winding Road of Cardiac Regeneration-Stem Cell Omics in the Spotlight. Cells 2018; 7:255. [PMID: 30544622 PMCID: PMC6315576 DOI: 10.3390/cells7120255] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/26/2018] [Accepted: 12/04/2018] [Indexed: 12/18/2022] Open
Abstract
Despite significant progress in treating ischemic cardiac disease and succeeding heart failure, there is still an unmet need to develop effective therapeutic strategies given the persistent high-mortality rate. Advances in stem cell biology hold great promise for regenerative medicine, particularly for cardiac regeneration. Various cell types have been used both in preclinical and clinical studies to repair the injured heart, either directly or indirectly. Transplanted cells may act in an autocrine and/or paracrine manner to improve the myocyte survival and migration of remote and/or resident stem cells to the site of injury. Still, the molecular mechanisms regulating cardiac protection and repair are poorly understood. Stem cell fate is directed by multifaceted interactions between genetic, epigenetic, transcriptional, and post-transcriptional mechanisms. Decoding stem cells' "panomic" data would provide a comprehensive picture of the underlying mechanisms, resulting in patient-tailored therapy. This review offers a critical analysis of omics data in relation to stem cell survival and differentiation. Additionally, the emerging role of stem cell-derived exosomes as "cell-free" therapy is debated. Last but not least, we discuss the challenges to retrieve and analyze the huge amount of publicly available omics data.
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Affiliation(s)
- Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
| | - Alina Ioana Scarlatescu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
| | - Alexandru Scafa-Udriste
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
- Department 4-Cardiothoracic Pathology, University of Medicine and Pharmacy Carol Davila, Eroii Sanitari Bvd. 8, 050474 Bucharest, Romania.
| | - Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Floreasca Street 8, 014461 Bucharest, Romania.
- Department 4-Cardiothoracic Pathology, University of Medicine and Pharmacy Carol Davila, Eroii Sanitari Bvd. 8, 050474 Bucharest, Romania.
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Narayanan S, Loganathan G, Mokshagundam S, Hughes MG, Williams SK, Balamurugan AN. Endothelial cell regulation through epigenetic mechanisms: Depicting parallels and its clinical application within an intra-islet microenvironment. Diabetes Res Clin Pract 2018; 143:120-133. [PMID: 29953914 DOI: 10.1016/j.diabres.2018.06.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/31/2018] [Accepted: 06/19/2018] [Indexed: 12/12/2022]
Abstract
The intra-islet endothelial cells (ECs), the building blocks of islet microvasculature, govern a number of cellular and pathophysiological processes associated with the pancreatic tissue. These cells are key to the angiogenic process and essential for islet revascularization after transplantation. Understanding fundamental mechanisms by which ECs regulate the angiogenic process is important as these cells maintain and regulate the intra-islet environment facilitated by a complex signaling crosstalk with the surrounding endocrine cells. In recent years, many studies have demonstrated the impact of epigenetic regulation on islet cell development and function. This review will present an overview of the reports involving endothelial epigenetic mechanisms particularly focusing on histone modifications which have been identified to play a critical role in governing EC functions by modifying the chromatin structure. A better understanding of epigenetic mechanisms by which these cells regulate gene expression and function to orchestrate cellular physiology and pathology is likely to offer improved insights on the functioning and regulation of an intra-islet endothelial microvascular environment.
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Affiliation(s)
- Siddharth Narayanan
- Clinical Islet Cell Laboratory, Center for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY 40202, United States
| | - Gopalakrishnan Loganathan
- Clinical Islet Cell Laboratory, Center for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY 40202, United States
| | | | - Michael G Hughes
- Clinical Islet Cell Laboratory, Center for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY 40202, United States
| | - Stuart K Williams
- Department of Physiology, University of Louisville, Louisville, KY 40202, United States
| | - Appakalai N Balamurugan
- Clinical Islet Cell Laboratory, Center for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY 40202, United States.
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Ort C, Dayekh K, Xing M, Mequanint K. Emerging Strategies for Stem Cell Lineage Commitment in Tissue Engineering and Regenerative Medicine. ACS Biomater Sci Eng 2018; 4:3644-3657. [PMID: 33429592 DOI: 10.1021/acsbiomaterials.8b00532] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Stem cells have transformed the fields of tissue engineering and regenerative medicine, and their potential to further advance these fields cannot be overstated. The stem cell niche is a dynamic microenvironment that determines cell fate during development and tissue repair following an injury. Classically, stem cells were studied in isolation of their microenvironment; however, contemporary research has produced a myriad of evidence that shows the importance of multiple aspects of the stem cell niche in regulating their processes. In the context of tissue engineering and regenerative medicine studies, the niche is an artificial environment provided by culture conditions. In vitro culture conditions may involve coculturing with other cell types, developing specific biomaterials, and applying relevant forces to promote the desired lineage commitment. Considerable advance has been made over the past few years toward directed stem cell differentiation; however, the unspecific differentiation of stem cells yielding a mixed population of cells has been a challenge. In this review, we provide a systematic review of the emerging strategies used for lineage commitment within the context of tissue engineering and regenerative medicine. These strategies include scaffold pore-size and pore-shape gradients, stress relaxation, sonic and electromagnetic effects, and magnetic forces. Finally, we provide insights and perspectives into future directions focusing on signaling pathways activated during lineage commitment using external stimuli.
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Affiliation(s)
| | | | - Malcolm Xing
- Department of Mechanical Engineering, University of Manitoba, 66 Chancellors Circle, Winnipeg R3T 2N2, Canada
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42
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Endothelial cell senescence in aging-related vascular dysfunction. Biochim Biophys Acta Mol Basis Dis 2018; 1865:1802-1809. [PMID: 31109450 DOI: 10.1016/j.bbadis.2018.08.008] [Citation(s) in RCA: 266] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/31/2018] [Accepted: 08/02/2018] [Indexed: 12/20/2022]
Abstract
Increased cardiovascular disease in aging is partly a consequence of the vascular endothelial cell (EC) senescence and associated vascular dysfunction. In this contest, EC senescence is a pathophysiological process of structural and functional changes including dysregulation of vascular tone, increased endothelium permeability, arterial stiffness, impairment of angiogenesis and vascular repair, and a reduction of EC mitochondrial biogenesis. Dysregulation of cell cycle, oxidative stress, altered calcium signaling, hyperuricemia, and vascular inflammation have been implicated in the development and progression of EC senescence and vascular disease in aging. A number of abnormal molecular pathways are associated with these underlying pathophysiological changes including Sirtuin 1, Klotho, fibroblast growth factor 21, and activation of the renin angiotensin-aldosterone system. However, the molecular mechanisms of EC senescence and associated vascular impairment in aging are not completely understood. This review provides a contemporary update on molecular mechanisms, pathophysiological events, as well functional changes in EC senescence and age-associated cardiovascular disease. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang.
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Liu F, Kc P, Ni L, Zhang G, Zhe J. A microfluidic competitive immuno-aggregation assay for high sensitivity cell secretome detection. Organogenesis 2018; 14:67-81. [PMID: 29883244 DOI: 10.1080/15476278.2018.1461306] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We report a high-sensitivity cell secretome detection method using competitive immuno-aggregation and a micro-Coulter counter. A target cell secretome protein competes with anti-biotin-coated microparticles (MPs) to bind with a biotinylated antibody (Ab), causing decreased aggregation of the functionalized MPs and formation of a mixture of MPs and aggregates. In comparison, without the target cell secretome protein, more microparticles are functionalized, and more aggregates are formed. Thus, a decrease in the average volume of functionalized microparticles/aggregates indicates an increase in cell secretome concentration. This volume change is measured by the micro-Coulter counter, which is used to quantitatively estimate the cell secretome concentration. Vascular endothelial growth factor (VEGF), one of the key cell secretome proteins that regulate angiogenesis and vascular permeabilization, was used as the target protein to demonstrate the sensing principle. A standard calibration curve was generated by testing samples with various VEGF concentrations. A detection range from 0.01 ng/mL to 100.00 ng/mL was achieved. We further demonstrated the quantification of VEGF concentration in exogenous samples collected from the secretome of human mesenchymal stem cells (hMSCs) at different incubation times. The results from the assay agree well with the results of a parallel enzyme-linked immunoabsorbent assay (ELISA) test, indicating the specificity and reliability of the competitive immuno-aggregation assay. With its simple structure and easy sample preparation, this assay not only enables high sensitivity detection of VEGF but also can be readily extended to other types of cell secretome analysis as long as the specific Ab is known.
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Affiliation(s)
- Fan Liu
- a Department of Mechanical Engineering , The University of Akron , Akron , Ohio , United States
| | - Pawan Kc
- b Department of Biomedical Engineering , The University of Akron , Akron , Ohio , United States
| | - Liwei Ni
- a Department of Mechanical Engineering , The University of Akron , Akron , Ohio , United States
| | - Ge Zhang
- b Department of Biomedical Engineering , The University of Akron , Akron , Ohio , United States
| | - Jiang Zhe
- a Department of Mechanical Engineering , The University of Akron , Akron , Ohio , United States
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Abstract
Vascular, resident stem cells are present in all 3 layers of the vessel wall; they play a role in vascular formation under physiological conditions and in remodeling in pathological situations. Throughout development and adult early life, resident stem cells participate in vessel formation through vasculogenesis and angiogenesis. In adults, the vascular stem cells are mostly quiescent in their niches but can be activated in response to injury and participate in endothelial repair and smooth muscle cell accumulation to form neointima. However, delineation of the characteristics and of the migration and differentiation behaviors of these stem cells is an area of ongoing investigation. A set of genetic mouse models for cell lineage tracing has been developed to specifically address the nature of these cells and both migration and differentiation processes during physiological angiogenesis and in vascular diseases. This review summarizes the current knowledge on resident stem cells, which has become more defined and refined in vascular biology research, thus contributing to the development of new potential therapeutic strategies to promote endothelial regeneration and ameliorate vascular disease development.
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Affiliation(s)
- Li Zhang
- From the Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z., T.C., Q.X.)
| | - Shirin Issa Bhaloo
- School of Cardiovascular Medicine and Sciences, King’s College London, BHF Centre, United Kingdom (S.I.B., Q.X.)
| | - Ting Chen
- From the Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z., T.C., Q.X.)
| | - Bin Zhou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academic of Sciences (B.Z.)
| | - Qingbo Xu
- From the Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z., T.C., Q.X.)
- School of Cardiovascular Medicine and Sciences, King’s College London, BHF Centre, United Kingdom (S.I.B., Q.X.)
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Wang J, Jin X, Huang Y, Ran X, Luo D, Yang D, Jia D, Zhang K, Tong J, Deng X, Wang G. Endovascular stent-induced alterations in host artery mechanical environments and their roles in stent restenosis and late thrombosis. Regen Biomater 2018; 5:177-187. [PMID: 29942650 PMCID: PMC6007795 DOI: 10.1093/rb/rby006] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/11/2018] [Accepted: 03/08/2018] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular stent restenosis remains a major challenge in interventional treatment of cardiovascular occlusive disease. Although the changes in arterial mechanical environment due to stent implantation are the main causes of the initiation of restenosis and thrombosis, the mechanisms that cause this initiation are still not fully understood. In this article, we reviewed the studies on the issue of stent-induced alterations in arterial mechanical environment and discussed their roles in stent restenosis and late thrombosis from three aspects: (i) the interaction of the stent with host blood vessel, involve the response of vascular wall, the mechanism of mechanical signal transmission, the process of re-endothelialization and late thrombosis; (ii) the changes of hemodynamics in the lumen of the vascular segment and (iii) the changes of mechanical microenvironment within the vascular segment wall due to stent implantation. This review has summarized and analyzed current work in order to better solve the two main problems after stent implantation, namely in stent restenosis and late thrombosis, meanwhile propose the deficiencies of current work for future reference.
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Affiliation(s)
- Jinxuan Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Xuepu Jin
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Yuhua Huang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Xiaolin Ran
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Desha Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Dongchuan Yang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Dongyu Jia
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Kang Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
| | - Jianhua Tong
- Institute for Biomedical Engineering & Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoyan Deng
- Key Laboratory for Biomechanics and Mechanobiology of the Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Guixue Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education; State and Local Joint Engineering Laboratory for Vascular Implants; Bioengineering College of Chongqing University, Chongqing, China
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Zhang Y, Zheng X, Tan H, Lu Y, Tao D, Liu Y, Ma Y. PIWIL2 suppresses Siah2-mediated degradation of HDAC3 and facilitates CK2α-mediated HDAC3 phosphorylation. Cell Death Dis 2018; 9:423. [PMID: 29555935 PMCID: PMC5859188 DOI: 10.1038/s41419-018-0462-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/26/2018] [Accepted: 03/02/2018] [Indexed: 02/05/2023]
Abstract
HDAC3 is involved in deacetylation of histone and non-histone proteins, having a key role in the regulation of gene transcription and also in the process of tumorgenesis. However, how HDAC3 is regulated in cancer remains largely unclear. Here, we showed that PIWIL2 can interact with HDAC3, leading to stabilization of HDAC3 from ubiquitin-mediated degradation by competitive association with E3 ubiquitin ligase Siah2. Furthermore, we found that expression of PIWIL2 enhanced HDAC3 activity via CK2α. PIWIL2 facilitated the interaction between HDAC3 and CK2α, thus exhibiting a promotion on the HDAC3 phosphorylation by CK2α. Further work showed that PIWIL2 could promote cell proliferation and suppress cell apoptosis via regulating HDAC3. Our present study firstly revealed that PIWIL2 can play a role in HDAC3-mediated epigenetic regulation on cancer cell proliferation and apoptosis. These findings provide a novel insight into the roles of PIWIL2 in tumorigenesis.
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Affiliation(s)
- Yingying Zhang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Xulei Zheng
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Hao Tan
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Yilu Lu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Dachang Tao
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Yunqiang Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Yongxin Ma
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China.
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Schiattarella GG, Madonna R, Van Linthout S, Thum T, Schulz R, Ferdinandy P, Perrino C. Epigenetic modulation of vascular diseases: Assessing the evidence and exploring the opportunities. Vascul Pharmacol 2018; 107:S1537-1891(17)30468-8. [PMID: 29548901 DOI: 10.1016/j.vph.2018.02.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 01/27/2018] [Accepted: 02/22/2018] [Indexed: 02/09/2023]
Abstract
Vascular adaptations to either physiological or pathophysiological conditions commonly require gene expression modifications in the most represented cellular elements of the vessel wall, i.e. endothelial and smooth muscle cells. In addition to transcription factors, a number of mechanisms contribute to the regulation of gene expression in these cells including noncoding RNAs, histone and DNA modifications, collectively indicated as epigenetic modifications. Here, we summarize the state of art regarding the role of epigenetic changes in major vascular diseases, and discuss the potential diagnostic and therapeutic applications of epigenetic modulation in this context.
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Affiliation(s)
| | - Rosalinda Madonna
- Center for Aging Sciences and Translational Medicine - CESI-MeT, Institute of Cardiology, Department of Neurosciences, Imaging and Clinical Sciences, "G. D'Annunzio" University, Chiety, Italy; Center for Cardiovascular Biology and Atherosclerosis Research, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Sophie Van Linthout
- Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Berlin, Germany; Charité University Medicine Berlin, Campus Rudolf Virchow, Department of Cardiology, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig University of Giessen, Giessen, Germany
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary; Pharmahungary Group, Szeged, Hungary
| | - Cinzia Perrino
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
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Shear stress: An essential driver of endothelial progenitor cells. J Mol Cell Cardiol 2018; 118:46-69. [PMID: 29549046 DOI: 10.1016/j.yjmcc.2018.03.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/08/2018] [Accepted: 03/09/2018] [Indexed: 02/06/2023]
Abstract
The blood flow through vessels produces a tangential, or shear, stress sensed by their innermost layer (i.e., endothelium) and representing a major hemodynamic force. In humans, endothelial repair and blood vessel formation are mainly performed by circulating endothelial progenitor cells (EPCs) characterized by a considerable expression of vascular endothelial growth factor receptor 2 (VEGFR2), CD34, and CD133, pronounced tube formation activity in vitro, and strong reendothelialization or neovascularization capacity in vivo. EPCs have been proposed as a promising agent to induce reendothelialization of injured arteries, neovascularization of ischemic tissues, and endothelialization or vascularization of bioartificial constructs. A number of preconditioning approaches have been suggested to improve the regenerative potential of EPCs, including the use of biophysical stimuli such as shear stress. However, in spite of well-defined influence of shear stress on mature endothelial cells (ECs), articles summarizing how it affects EPCs are lacking. Here we discuss the impact of shear stress on homing, paracrine effects, and differentiation of EPCs. Unidirectional laminar shear stress significantly promotes homing of circulating EPCs to endothelial injury sites, induces anti-thrombotic and anti-atherosclerotic phenotype of EPCs, increases their capability to form capillary-like tubes in vitro, and enhances differentiation of EPCs into mature ECs in a dose-dependent manner. These effects are mediated by VEGFR2, Tie2, Notch, and β1/3 integrin signaling and can be abrogated by means of complementary siRNA/shRNA or selective pharmacological inhibitors of the respective proteins. Although the testing of sheared EPCs for vascular tissue engineering or regenerative medicine applications is still an unaccomplished task, favorable effects of unidirectional laminar shear stress on EPCs suggest its usefulness for their preconditioning.
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Whole-Transcriptome Sequencing: a Powerful Tool for Vascular Tissue Engineering and Endothelial Mechanobiology. High Throughput 2018; 7:ht7010005. [PMID: 29485616 PMCID: PMC5876531 DOI: 10.3390/ht7010005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 02/18/2018] [Accepted: 02/19/2018] [Indexed: 02/07/2023] Open
Abstract
Among applicable high-throughput techniques in cardiovascular biology, whole-transcriptome sequencing is of particular use. By utilizing RNA that is isolated from virtually all cells and tissues, the entire transcriptome can be evaluated. In comparison with other high-throughput approaches, RNA sequencing is characterized by a relatively low-cost and large data output, which permits a comprehensive analysis of spatiotemporal variation in the gene expression profile. Both shear stress and cyclic strain exert hemodynamic force upon the arterial endothelium and are considered to be crucial determinants of endothelial physiology. Laminar blood flow results in a high shear stress that promotes atheroresistant endothelial phenotype, while a turbulent, oscillatory flow yields a pathologically low shear stress that disturbs endothelial homeostasis, making respective arterial segments prone to atherosclerosis. Severe atherosclerosis significantly impairs blood supply to the organs and frequently requires bypass surgery or an arterial replacement surgery that requires tissue-engineered vascular grafts. To provide insight into patterns of gene expression in endothelial cells in native or bioartificial arteries under different biomechanical conditions, this article discusses applications of whole-transcriptome sequencing in endothelial mechanobiology and vascular tissue engineering.
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50
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Yang J, Xu J, Danniel M, Wang X, Wang W, Zeng L, Shen L. The interaction between XBP1 and eNOS contributes to endothelial cell migration. Exp Cell Res 2018; 363:262-270. [PMID: 29352987 DOI: 10.1016/j.yexcr.2018.01.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/03/2018] [Accepted: 01/12/2018] [Indexed: 11/29/2022]
Abstract
The X-box binding protein 1 (XBP1) is a pivotal transcription factor in the endoplasmic reticulum stress response. Our previous studies have proven that XBP1 is involved in vascular endothelial growth factor (VEGF)-mediated endothelial cell (EC) proliferation and angiogenesis. In this study, we used EC monolayer wound healing, tube formation and transwell migration models to explore the role of XBP1splicing in EC migration. We found that scratching on EC monolayer triggered XBP1splicing, which was attenuated by the presence of SU5416and LY294002, suggesting that VEGF signalling pathways may be involved. Over-expression of the spliced XBP1 (XBP1s) via Ad-XBP1s gene transfer increased while knockdown of IRE1αor XBP1 by ShRNA lentivirus suppressed EC migration. Over-expression of XBP1s up-regulated the nitric oxide synthase 3 (NOS3)mRNA through the 3'UTR-mediated stabilisation and increased eNOS protein translation. Further experiments demonstrated that miR-24 participated in the XBP1s-induced eNOSup-regulation and EC migration. Further co-IP and immunofluorescence staining assays revealed that protein kinase B (Akt), eNOS andXBP1s form a complex, resulting in Akt and eNOS nucleus relocation. These results suggest that XBP1 splicing can regulate eNOS expression and cellular location, leading to EC migration and therefore contributing to wound healing and angiogenesis.
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Affiliation(s)
- Junyao Yang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Cardiovascular Division, Faculty of Life Science and Medicine, King's College London, SE5 9NU London, United Kingdom
| | - Jing Xu
- School of Engineering and Materials Science, Queen Mary, University of London, E1 4NS London, United Kingdom
| | - Martin Danniel
- Cardiovascular Division, Faculty of Life Science and Medicine, King's College London, SE5 9NU London, United Kingdom
| | - Xiaocong Wang
- Cardiovascular Division, Faculty of Life Science and Medicine, King's College London, SE5 9NU London, United Kingdom
| | - Wen Wang
- School of Engineering and Materials Science, Queen Mary, University of London, E1 4NS London, United Kingdom
| | - Lingfang Zeng
- Cardiovascular Division, Faculty of Life Science and Medicine, King's College London, SE5 9NU London, United Kingdom.
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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