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Zhan X, Zhong CM, Tang H, Xiao H, Guo Y, Zhang C, Qu C, Wang X, Huang C. microRNA-18a-5p promotes vascular smooth muscle cell phenotypic switch by targeting Notch2 as therapeutic targets in vein grafts restenosis. Eur J Pharmacol 2024; 985:177097. [PMID: 39522684 DOI: 10.1016/j.ejphar.2024.177097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
Vascular smooth muscle cells (VSMCs) phenotype switching plays a crucial role in vein graft restenosis following coronary artery bypass grafting (CABG) surgery. To discover novel clinically relevant therapeutic targets for vein graft restenosis after CABG, we therefore investigated whether miRNA-18a-5p mediated phenotype switching plays a critical role in the development of vein graft restenosis. We studied miRNA-18a-5p expression in plasma samples of patients with or without vein graft restenosis at 1, 3 and 5 years after coronary artery bypass graft surgery, and in normal vs. atherosclerotic human femoral artery samples, to prove its role in VSMC phenotype switching. We found that the expression of miRNA-18a-5p significantly increased in vein grafts restenosis rat model after bypass surgery at 7, 14, 28 days and human blood specimens with vein grafts failure after grafting surgery. Through gain- and loss-of-function approaches, we determined that miRNA-18a-5p affects VSMC proliferation, migration, differentiation, and contractility. Notch2 was found to be a direct target of miRNA-18a-5p, which is critical for VSMC phenotype switching. Finally, miRNA-18a-5p knockdown used miRNA sponge via AAV6 locally delivery in vivo, miRNA-18a-5p sponge gene transfer therapy reduced the neointimal area, neointimal thickness, and intimal/media area ratio in vein grafts compared with the controls and improved vein graft hemodynamics. miRNA-18a-5p is a critical modulator of VSMC phenotypic switch during development of vein graft restenosis by downregulating Notch2, therefore targeting miRNA-18a-5p may be a helpful strategy for the treatment of vein grafts restenosis or failure after CABG surgery.
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MESH Headings
- MicroRNAs/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Animals
- Humans
- Receptor, Notch2/genetics
- Receptor, Notch2/metabolism
- Rats
- Male
- Phenotype
- Graft Occlusion, Vascular/genetics
- Graft Occlusion, Vascular/pathology
- Graft Occlusion, Vascular/metabolism
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Cell Proliferation/genetics
- Rats, Sprague-Dawley
- Coronary Artery Bypass/adverse effects
- Cell Movement/genetics
- Neointima/pathology
- Coronary Restenosis/genetics
- Coronary Restenosis/etiology
- Coronary Restenosis/pathology
- Coronary Restenosis/metabolism
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Affiliation(s)
- Xu Zhan
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Chang-Ming Zhong
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hao Tang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hansong Xiao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yongzheng Guo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Cheng Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Centre for Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
| | - Can Qu
- Division of Pharmacology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xiaowen Wang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Chun Huang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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2
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Song J, Shao J, Yu S, Zhang H, Wang J. LncRNA MEG3 aggravates acute pulmonary embolism-induced pulmonary arterial hypertension by regulating miR-34a-3p/DUSP1 axis. Int J Biol Macromol 2024; 283:137755. [PMID: 39551320 DOI: 10.1016/j.ijbiomac.2024.137755] [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: 10/02/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Acute pulmonary embolism (APE)-induced pulmonary artery hypertension (PAH) is a fatal disease. The miR-34-3p/DUSP1 has inhibitory effects on the thickening of the pulmonary arterial walls in APE rats and the proliferation of platelet-derived growth factor-BB (PDGF-BB)-induced human pulmonary arterial smooth muscle cells (hPASMCs). Herein, the lncRNAs regulating the miR-34a-3p/DUSP1 axis in APE and PAH are further explored in vitro and in vivo. MEG3 targeted miR-34a-3p. MEG3 overexpression potentiated the effects of PDGF-BB treatment on promoting the viability and proliferation of hPASMCs, as well as the mPAP level in APE rats. Also, overexpressed MEG3 strengthened PDGF-BB-induced upregulation of MEG3, NOR-1, PCNA and DUSP1, as well as downregulation of miR-34a-3p in hPASMCs and APE rats. However, shMEG3 generated opposite effects. MiR-34a-3p mimic reversed the effect of MEG3 overexpression, and DUSP1 overexpression neutralized the effect of MEG3 downregulation on PDGF-BB-induced hPASMCs and APE rats.MEG3 aggravates APE-induced PAH by regulating miR-34a-3p/DUSP1 axis, holding a great promise as a novel biomarker for PAH treatment.
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Affiliation(s)
- Jianfeng Song
- Emergency Department, Minhang Hospital, Fudan University, 170 Xinsong Road, Minhang District, Shanghai 201199, PR China
| | - Jinyan Shao
- Emergency Department, Minhang Hospital, Fudan University, 170 Xinsong Road, Minhang District, Shanghai 201199, PR China
| | - Shuili Yu
- Emergency Department, Minhang Hospital, Fudan University, 170 Xinsong Road, Minhang District, Shanghai 201199, PR China
| | - Heng Zhang
- Emergency Department, Minhang Hospital, Fudan University, 170 Xinsong Road, Minhang District, Shanghai 201199, PR China.
| | - Jiqin Wang
- Emergency Department, Minhang Hospital, Fudan University, 170 Xinsong Road, Minhang District, Shanghai 201199, PR China.
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He P, Yang Z, Li H, Zhou E, Hou Z, Sang H. miR-18a-5p promotes osteogenic differentiation of BMSC by inhibiting Notch2. Bone 2024; 188:117224. [PMID: 39117162 DOI: 10.1016/j.bone.2024.117224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/17/2024] [Accepted: 08/03/2024] [Indexed: 08/10/2024]
Abstract
Postmenopausal osteoporosis (PMOP) is a metabolic disorder characterized by the loss of bone density, which increases the risk of developing complications such as fractures. A pivotal factor contributing to the onset of PMOP is the diminished osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs). MicroRNAs (miRNAs) play a substantial role in this process; however, their specific impact on regulating BMSCs osteogenesis remains unclear. Studies have evidenced a reduced expression of miR-18a-5p in PMOP, and concomitantly, our observations indicate an augmented expression of miR-18a-5p during the osteogenic differentiation of BMSCs. This investigation seeks to elucidate the regulatory influence of miR-18a-5p on BMSC osteogenic differentiation and the underlying mechanisms. In vitro experiments demonstrated that the overexpression of miR-18a-5p facilitated the osteogenic differentiation of BMSCs, while the downregulation of miR-18a-5p yielded converse outcomes. Mechanistically, We employed bioinformatics techniques to screen out the target gene Notch2 of miR-18a-5p. Subsequently, dual-luciferase reporter gene assays and rescue experiments substantiated that miR-18a-5p promotes BMSC osteogenic differentiation by suppressing Notch2. Finally, miR-18a-5p was overexpressed via adenovirus injection into the femoral bone marrow cavity, with results demonstrating its capability to enhance osteogenic differentiation and alleviate PMOP symptoms. Our findings disclose that miR-18a-5p fosters osteogenic differentiation of BMSC by inhibiting Notch2, thereby offering novel targets and strategies for PMOP treatment.
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Affiliation(s)
- Peipei He
- Department of Orthopedics, Shenzhen Hospital, Southern Medical University, Shenzhen, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zefeng Yang
- Department of Orthopedics, Shenzhen Hospital, Southern Medical University, Shenzhen, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hetong Li
- Department of Orthopedics, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Enhui Zhou
- Department of Orthopedics, Shenzhen Hospital, Southern Medical University, Shenzhen, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zuoxu Hou
- Department of Orthopedics, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Hongxun Sang
- Department of Orthopedics, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
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Chen B, Xia Y, Jiang Y, Sun Z, Zhang Y, Liu Y. Non-Coding RNA Networks in Pulmonary Arterial Hypertension. Pharmacology 2024; 110:110-121. [PMID: 39342938 DOI: 10.1159/000541060] [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: 02/04/2024] [Accepted: 08/20/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Pulmonary artery hypertension (PAH) is a severe cardiovascular disease marked by a persistent increase in pulmonary artery resistance and pressure, leading to right ventricular strain, hypertrophy, and eventually right heart failure and death. Despite numerous available targeted therapies, the clinical needs for treating PAH remain unmet. Current treatments primarily aim to dilate pulmonary vessels rather than reverse pulmonary vascular remodeling, failing to offer a fundamental solution for PAH. Therefore, developing new therapies for this condition is urgently required. SUMMARY Recent research has highlighted the crucial role of non-coding RNAs (ncRNAs) in the occurrence and development of PAH. NcRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs), are a class of transcripts that do not translate proteins but affect various diseases at different levels, including chromatin modification, transcription regulation, post-translational processes. KEY MESSAGE The current study delves into recent advancements in understanding how lncRNAs, circRNAs, miRNAs, and piRNAs contribute to the pathogenesis of PAH. This review addresses the existing research challenges and explores the potential of ncRNAs as both biomarkers and therapeutic targets, suggesting that ncRNAs may serve as valuable indicators and treatment options for the disease.
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Affiliation(s)
- Bing Chen
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, China,
| | - Yu Xia
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, China
| | - Yanjiao Jiang
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, China
| | - Zengxian Sun
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, China
| | - Yanyan Zhang
- Department of Geriatrics, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, China
| | - Yun Liu
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, China
- Department of Pharmacy, Lianyungang Clinical College of Nanjing Medical University/The First People's Hospital of Lianyungang, Lianyungang, China
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5
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Zhou R, Li R, Ding Q, Zhang Y, Yang H, Han Y, Liu C, Liu J, Wang S. OPN silencing reduces hypoxic pulmonary hypertension via PI3K-AKT-induced protective autophagy. Sci Rep 2024; 14:8670. [PMID: 38622371 PMCID: PMC11018812 DOI: 10.1038/s41598-024-59367-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 04/09/2024] [Indexed: 04/17/2024] Open
Abstract
Hypoxic pulmonary hypertension (HPH) is a pulmonary vascular disease primarily characterized by progressive pulmonary vascular remodeling in a hypoxic environment, posing a significant clinical challenge. Leveraging data from the Gene Expression Omnibus (GEO) and human autophagy-specific databases, osteopontin (OPN) emerged as a differentially expressed gene, upregulated in cardiovascular diseases such as pulmonary arterial hypertension (PAH). Despite this association, the precise mechanism by which OPN regulates autophagy in HPH remains unclear, prompting the focus of this study. Through biosignature analysis, we observed significant alterations in the PI3K-AKT signaling pathway in PAH-associated autophagy. Subsequently, we utilized an animal model of OPNfl/fl-TAGLN-Cre mice and PASMCs with OPN shRNA to validate these findings. Our results revealed right ventricular hypertrophy and elevated mean pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension model mice. Notably, these effects were attenuated in conditionally deleted OPN-knockout mice or OPN-silenced hypoxic PASMCs. Furthermore, hypoxic PASMCs with OPN shRNA exhibited increased autophagy compared to those in hypoxia alone. Consistent findings from in vivo and in vitro experiments indicated that OPN inhibition during hypoxia reduced PI3K expression while increasing LC3B and Beclin1 expression. Similarly, PASMCs exposed to hypoxia and PI3K inhibitors had higher expression levels of LC3B and Beclin1 and suppressed AKT expression. Based on these findings, our study suggests that OPNfl/fl-TAGLN-Cre effectively alleviates HPH, potentially through OPN-mediated inhibition of autophagy, thereby promoting PASMCs proliferation via the PI3K-AKT signaling pathway. Consequently, OPN emerges as a novel therapeutic target for HPH.
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Affiliation(s)
- Rui Zhou
- Qinghai University Medical Department, Xining, 810016, China
| | - Ran Li
- Zhengzhou Medical and Health Vocational College, Zhengzhou, 452385, China
| | - Qi Ding
- Pathology Department of Tianjin Huanghe Hospital, Tianjin, 300110, China
| | - Yuwei Zhang
- Department of Public Health, School of Medical, Qinghai University, Xining, 810016, China
| | - Hui Yang
- Qinghai University Medical Department, Xining, 810016, China
| | - Ying Han
- Qinghai University Medical Department, Xining, 810016, China
| | - Chuanchuan Liu
- Key Laboratory of Hydatid Disease, Qinghai University, Xining, 810001, China
| | - Jie Liu
- Qinghai University Medical Department, Xining, 810016, China
| | - Shenglan Wang
- Qinghai University Medical Department, Xining, 810016, China.
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6
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Ejaz M, Usman SM, Amir S, Khan MJ. Holistic expression of miR-17-92 cluster in obesity, kidney diseases, cardiovascular diseases, and diabetes. Mol Biol Rep 2023; 50:6913-6925. [PMID: 37329480 DOI: 10.1007/s11033-023-08549-4] [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: 04/09/2023] [Accepted: 05/24/2023] [Indexed: 06/19/2023]
Abstract
miR-17-92 cluster encodes six micro RNAs (miRNAs) and plays a crucial role in the regulation of various cellular processes. Aberrant expression of this cluster may result in the onset of several diseases. Initially, the role of miR-17-92 cluster in tumorigenesis was discovered but recent research has also uncovered its role in other diseases. Members of the cluster may serve as potential biomarkers in the prognosis, diagnosis, and treatment of several diseases and their complications. In this article, we have reviewed the recent research carried out on the expression pattern of miR-17-92 cluster in non-communicable diseases i.e., obesity, cardiovascular diseases (CVD), kidney diseases (KD) and diabetes mellitus (DM). We examined miR-17-92 role in pathological processes and their potential importance as biomarkers. Each member of the cluster miR-17-92 was upregulated in obesity. miR-18a, miR-19b-3p, miR20a, and miR92a were significantly upregulated in CVD. An equal fraction of the cluster was dysregulated (upregulated and downregulated) in diabetes; however, miR-17-92 was downregulated in most studies on CKD.
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Affiliation(s)
- Maheen Ejaz
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad Islamabad, Islamabad, 45550, Pakistan
| | - Syed Mohammad Usman
- Department of Biochemistry, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Saira Amir
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad Islamabad, Islamabad, 45550, Pakistan
| | - Muhammad Jawad Khan
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad Islamabad, Islamabad, 45550, Pakistan.
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Wang D, Luo MY, Tian Y, Zhang J, Liang N, Li NP, Gong SX, Wang AP. Critical miRNAs in regulating pulmonary hypertension: A focus on Signaling pathways and therapeutic Targets. Anal Biochem 2023:115228. [PMID: 37393975 DOI: 10.1016/j.ab.2023.115228] [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: 04/16/2023] [Revised: 06/19/2023] [Accepted: 06/29/2023] [Indexed: 07/04/2023]
Abstract
Pulmonary hypertension (PH) is complex disease as a result of obstructive pulmonary arterial remodeling, which in turn results in elevated pulmonary arterial pressure (PAP) and subsequent right ventricular heart failure, eventually leading to premature death. However, there is still a lack of a diagnostic blood-based biomarker and therapeutic target for PH. Because of the difficulty of diagnosis, new and more easily accessible prevention and treatment strategy are being explored. New target and diagnosis biomarkers should also allow for early diagnosis. In biology, miRNAs are short endogenous RNA molecules that are not coding. It is known that miRNAs can regulate gene expression and affect a variety of biological processes. Besides, miRNAs have been proven to be a crucial factor in PH pathogenesis. miRNAs have various effects on pulmonary vascular remodeling and are expressed differentially in various pulmonary vascular cells. Nowadays, it has been shown to be critical in the functions of different miRNAs in the pathogenesis of PH. Therefore, clarifying the mechanism of miRNAs regulating pulmonary vascular remodeling is of great importance to explore new therapeutic targets of PH and improve the survival qualify and time of patients. This review is focused on the role, mechanism, and potential therapeutic targets of miRNAs in PH and puts forward possible clinical treatment strategies.
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Affiliation(s)
- Di Wang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China
| | - Meng-Yi Luo
- Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China; Institute of Clinical Research, Department of Clinical Laboratory, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, PR China
| | - Ying Tian
- Institute of Clinical Research, Department of Clinical Laboratory, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, PR China
| | - Jing Zhang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China
| | - Na Liang
- Department of Anesthesiology, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, PR China
| | - Nan-Ping Li
- Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China; Department of Anesthesiology, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, PR China
| | - Shao-Xin Gong
- Department of Pathology, First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China.
| | - Ai-Ping Wang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China; Institute of Clinical Research, Department of Clinical Laboratory, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, PR China.
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Xu WJ, Wu Q, He WN, Wang S, Zhao YL, Huang JX, Yan XS, Jiang R. Interleukin-6 and pulmonary hypertension: from physiopathology to therapy. Front Immunol 2023; 14:1181987. [PMID: 37449201 PMCID: PMC10337993 DOI: 10.3389/fimmu.2023.1181987] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Pulmonary hypertension (PH) is a progressive, pulmonary vascular disease with high morbidity and mortality. Unfortunately, the pathogenesis of PH is complex and remains unclear. Existing studies have suggested that inflammatory factors are key factors in PH. Interleukin-6 (IL-6) is a multifunctional cytokine that plays a crucial role in the regulation of the immune system. Current studies reveal that IL-6 is elevated in the serum of patients with PH and it is negatively correlated with lung function in those patients. Since IL-6 is one of the most important mediators in the pathogenesis of inflammation in PH, signaling mechanisms targeting IL-6 may become therapeutic targets for this disease. In this review, we detailed the potential role of IL-6 in accelerating PH process and the specific mechanisms and signaling pathways. We also summarized the current drugs targeting these inflammatory pathways to treat PH. We hope that this study will provide a more theoretical basis for targeted treatment in patients with PH in the future.
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Affiliation(s)
- Wei-Jie Xu
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiong Wu
- Department of Pulmonary and Critical Care Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Ni He
- Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shang Wang
- Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ya-Lin Zhao
- Department of Respiratory Critical Care Medicine, The First Hospital of Kunming, Kunming, China
| | - Jun-Xia Huang
- Department of Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xue-Shen Yan
- Department of Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Rong Jiang
- Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3959845. [PMID: 36593773 PMCID: PMC9805398 DOI: 10.1155/2022/3959845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 11/25/2022] [Accepted: 12/07/2022] [Indexed: 12/25/2022]
Abstract
Vascular remodeling refers to changes in the size, contraction, distribution, and flow rate of blood vessels and even changes in vascular function. Vascular remodeling can cause cardiovascular and cerebrovascular diseases. It can also lead to other systemic diseases, such as pulmonary hypertension, pulmonary atherosclerosis, chronic obstructive pulmonary disease, stroke, and ascites of broilers. Hypoxia is one of the main causes of vascular remodeling. Prolonged hypoxia or intermittent hypoxia can lead to loss of lung ventilation, causing respiratory depression, irregular respiratory rhythms, and central respiratory failure. Animals that are unable to adapt to the highland environment are also prone to sustained constriction of the small pulmonary arteries, increased resistance to pulmonary circulation, and impaired blood circulation, leading to pulmonary hypertension and right heart failure if they live in a highland environment for long periods of time. However, limited studies have been found on the relationship between hypoxia and vascular remodeling. Therefore, this review will explore the relationship between hypoxia and vascular remodeling from the aspects of endoplasmic reticulum stress, mitochondrial dysfunction, abnormal calcium channel, disordered cellular metabolism, abnormal expression of miRNA, and other factors. This will help to understand the detailed mechanism of hypoxia-mediated smooth muscle cell proliferation and vascular remodeling for the better treatment and management of diseases due to vascular remodeling.
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10
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Shu X, Chen XX, Kang XD, Ran M, Wang YL, Zhao ZK, Li CX. Identification of potential key molecules and signaling pathways for psoriasis based on weighted gene co-expression network analysis. World J Clin Cases 2022; 10:5965-5983. [PMID: 35949853 PMCID: PMC9254198 DOI: 10.12998/wjcc.v10.i18.5965] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/30/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Psoriasis is a chronic inflammatory skin disease, the pathogenesis of which is more complicated and often requires long-term treatment. In particular, moderate to severe psoriasis usually requires systemic treatment. Psoriasis is also associated with many diseases, such as cardiometabolic diseases, malignant tumors, infections, and mood disorders. Psoriasis can appear at any age, and lead to a substantial burden for individuals and society. At present, psoriasis is still a treatable, but incurable, disease. Previous studies have found that microRNAs (miRNAs) play an important regulatory role in the progression of various diseases. Currently, miRNAs studies in psoriasis and dermatology are relatively new. Therefore, the identification of key miRNAs in psoriasis is helpful to elucidate the molecular mechanism of psoriasis.
AIM To identify key molecular markers and signaling pathways to provide potential basis for the treatment and management of psoriasis.
METHODS The miRNA and mRNA data were obtained from the Gene Expression Omnibus database. Then, differentially expressed mRNAs (DEmRNAs) and differentially expressed miRNAs (DEmiRNAs) were screened out by limma R package. Subsequently, DEmRNAs were analyzed for Gene Ontology and Kyoto Encyclopedia of Genes and Genomics functional enrichment. The “WGCNA” R package was used to analyze the co-expression network of all miRNAs. In addition, we constructed miRNA-mRNA regulatory networks based on identified hub miRNAs. Finally, in vitro validation was performed. All experimental procedures were approved by the ethics committee of Chinese PLA General Hospital (S2021-012-01).
RESULTS A total of 639 DEmRNAs and 84 DEmiRNAs were identified. DEmRNAs screening criteria were adjusted P (adj. P) value < 0.01 and |logFoldChange| (|logFC|) > 1. DEmiRNAs screening criteria were adj. P value < 0.01 and |logFC| > 1.5. KEGG functional analysis demonstrated that DEmRNAs were significantly enriched in immune-related biological functions, for example, toll-like receptor signaling pathway, cytokine-cytokine receptor interaction, and chemokine signaling pathway. In weighted gene co-expression network analysis, turquoise module was the hub module. Moreover, 10 hub miRNAs were identified. Among these 10 hub miRNAs, only 8 hub miRNAs predicted the corresponding target mRNAs. 97 negatively regulated miRNA-mRNA pairs were involved in the miRNA-mRNA regulatory network, for example, hsa-miR-21-5p-claudin 8 (CLDN8), hsa-miR-30a-3p-interleukin-1B (IL-1B), and hsa-miR-181a-5p/hsa-miR-30c-2-3p-C-X-C motif chemokine ligand 9 (CXCL9). Real-time polymerase chain reaction results showed that IL-1B and CXCL9 were up-regulated and CLDN8 was down-regulated in psoriasis with statistically significant differences.
CONCLUSION The identification of potential key molecular markers and signaling pathways provides potential research directions for further understanding the molecular mechanisms of psoriasis. This may also provide new research ideas for the prevention and treatment of psoriasis in the future.
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Affiliation(s)
- Xin Shu
- Department of Dermatology, The Third Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- Chinese PLA Medical School, Beijing 100853, China
| | - Xiao-Xia Chen
- Department of Radiology, The Third Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Xin-Dan Kang
- Department of Comprehensive Surgical, The Second Medical Center of Chinese PLA General Hospital, Beijing 100089, China
| | - Min Ran
- Department of Endocrine, The Third Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - You-Lin Wang
- Department of Dermatology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Zhen-Kai Zhao
- Department of Dermatology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Cheng-Xin Li
- Department of Dermatology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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11
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Zhang Y, Ye Y, Li Z, Dai H, Wang P. miR-18a-5p Reduces Inflammatory Response and Human Dermal Microvascular Endothelial Cells Permeability by Targeting Thrombospondin 1 in Chronic Idiopathic Urticaria. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Chronic idiopathic urticaria (CIU) is a skin disease that has an acute attack when patient encounters an allergen. Previous research demonstrated that microRNA (miRNA) has a crucial role in CIU occurrence and development. This study aimed to investigate the role and mechanism of miR-18a-5p
in CIU. StarBase and dual luciferase reporter gene assay confirmed that thrombospondin 1 (THBS1) was a direct target of miR-18a-5p. miR-18a-5p negatively regulated THBS1 expression in human mast cell line HMC-1 and human dermal microvascular endothelial cells (HDMECs). Further analysis indicated
that miR-18a-5p mimic significantly reduced inflammatory factors including interleukin (IL)-6, IL-8, IL-1β and tumor necrosis factor (TNF)-α release, decreased the degranulation rate and histamine release rate of HMC-1 cells. Besides, we found that miR-18a-5p reduced
the permeability of HDMECs by suppressing THBS1 expression. Finally, the data indicated that miR-18a-5p inhibited the transforming growth factor beta (TGF-β)/SMAD family member 3 (Smad3) signaling pathway in HDMECs by inhibiting the expression of THBS1. Taken together, the results
suggested that miR-18a-5p reduced inflammation and human skin microvascular endothelial cell permeability in CIU by targeting THBS1. miR-18a-5p might be a new target for CIU treatment.
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Affiliation(s)
- Yijin Zhang
- Department of Dermetology, The Third People’s Hospital of Hangzhou, Hangzhuo 310000, China
| | - Yujian Ye
- Department of Dermetology, The Third People’s Hospital of Hangzhou, Hangzhuo 310000, China
| | - Zhao Li
- Department of Dermetology, The Third People’s Hospital of Hangzhou, Hangzhuo 310000, China
| | - Hui Dai
- Department of Dermetology, The Third People’s Hospital of Hangzhou, Hangzhuo 310000, China
| | - Ping Wang
- Department of Dermetology, The Third People’s Hospital of Hangzhou, Hangzhuo 310000, China
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12
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Li Y, Shao J, Song J, Yu S, Wang J, Sun K. MiR-34a-3p suppresses pulmonary vascular proliferation in acute pulmonary embolism rat by targeting DUSP1. Biosci Rep 2022; 42:BSR20210116. [PMID: 34778900 PMCID: PMC8703022 DOI: 10.1042/bsr20210116] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 09/07/2021] [Accepted: 09/14/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Acute pulmonary embolism (APE) is a prevalent reason of cardiovascular morbidity and mortality. Recent studies have underscored the positive effects of microRNAs (miRNAs) on many diseases. The present study aimed to identify the critical miRNA with differential expressions and explore its role in APE. METHODS The critical miRNA with its target gene was screened by bioinformatics analysis. Their binding relationship was analyzed by TargetScan, Dual-luciferase reporter and RNA pull-down assays. A rat model of APE was established by self-blood coagulum. Human pulmonary artery smooth muscle cells (PASMCs) were exposed to platelet-derived growth factor (PDGF-BB) for excessive proliferation, and transfected with miR-34a-3p mimic. Mean pulmonary arterial pressure (mPAP) of rat was measured, and the pulmonary tissues were used for the pathological observation by Hematoxylin-Eosin (H&E) staining. Cell viability and proliferation were detected by Cell Counting Kit-8 (CCK-8) and EdU assays. The expressions of miR-34a-3p with its target genes (including dual-specificity phosphatase-1 (DUSP1)), neuron-derived orphan receptor-1 (NOR-1) and proliferating cell nuclear antigen (PCNA) were determined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) or/and Western blot. RESULTS MiR-34a-3p expression was down-regulated in APE patients, which attenuated the increment of mPAP and thickening of the pulmonary arterial walls in APE rats, accompanied with regulation of NOR-1 and PCNA levels. MiR-34a-3p suppressed DUSP1 expression by directly binding to its 3'-untranslated region (UTR), and attenuated cell viability, proliferation, and the expressions of NOR-1 and PCNA in PDGF-BB-induced PASMCs by inhibiting DUSP1 expression. CONCLUSION Up-regulated miR-34a-3p negatively regulates DUSP1 expression to inhibit PASMC proliferation, which, thus, may act on APE treatment by negatively regulating pulmonary vascular proliferation.
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MESH Headings
- Animals
- Case-Control Studies
- Cell Proliferation
- Cells, Cultured
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Disease Models, Animal
- Dual Specificity Phosphatase 1/genetics
- Dual Specificity Phosphatase 1/metabolism
- Gene Expression Regulation, Enzymologic
- Male
- Membrane Transport Proteins/genetics
- Membrane Transport Proteins/metabolism
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Proliferating Cell Nuclear Antigen/genetics
- Proliferating Cell Nuclear Antigen/metabolism
- Pulmonary Artery/enzymology
- Pulmonary Artery/pathology
- Pulmonary Embolism/enzymology
- Pulmonary Embolism/genetics
- Pulmonary Embolism/pathology
- Rats, Sprague-Dawley
- Signal Transduction
- Vascular Remodeling
- Rats
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Affiliation(s)
- Yang Li
- Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
| | - Jinyan Shao
- Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
| | - Jianfeng Song
- Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
| | - Shuili Yu
- Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
| | - Jiqin Wang
- Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
| | - Keyu Sun
- Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
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13
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Leonova A, Turpin VE, Agarwal SK, Leonardi M, Foster WG. A critical appraisal of the circulating levels of differentially expressed microRNA in endometriosis†. Biol Reprod 2021; 105:1075-1085. [PMID: 34244742 PMCID: PMC8599033 DOI: 10.1093/biolre/ioab134] [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: 04/15/2021] [Revised: 06/07/2021] [Accepted: 07/02/2021] [Indexed: 01/23/2023] Open
Abstract
Endometriosis is a common gynecological condition characterized by estrogen dependence, chronic pelvic pain, infertility, and diagnostic delay of between 5.4 and 12 years. Despite extensive study, no biomarker, either alone or in combination with other markers, has proven superior to laparoscopy for the diagnosis of endometriosis. Recent studies report that circulating levels of differentially expressed microRNA (miRNA) in women with endometriosis compared with controls are potential diagnostic tools. However, the lack of replication and absence of validated differential expression in novel study populations have led some to question the diagnostic value of miRNA. To elucidate potential reasons for the lack of replication of study results and explore future directions to enhance replicability of circulating miRNA results, we carried out an electronic search of the miRNA literature published between 2000 and 2020. Eighteen studies were identified in which 63 different miRNAs were differentially expressed in the circulation of women with endometriosis compared with controls. However, the differential expressions of only 14 miRNAs were duplicated in one or more studies. While individual miRNAs lacked diagnostic value, miRNA panels yielded sensitivity and specificity equal to or better than laparoscopy in five studies. Important differences in study design, sample processing, and analytical methods were identified rendering direct comparisons across studies problematic and could account for the lack of reproducibility of study results. We conclude that while the results of miRNA studies to date are encouraging, refinements to study design and analytical methods should enhance the reliability of circulating miRNA for the diagnosis of endometriosis.
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Affiliation(s)
- Anna Leonova
- Department of Obstetrics and Gynaecology, McMaster University, Hamilton, Ontario, Canada
| | - Victoria E Turpin
- Department of Obstetrics and Gynaecology, McMaster University, Hamilton, Ontario, Canada
| | - Sanjay K Agarwal
- Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Endometriosis Research and Treatment, University of California San Diego, San Diego, California, USA
| | - Mathew Leonardi
- Department of Obstetrics and Gynaecology, McMaster University, Hamilton, Ontario, Canada
| | - Warren G Foster
- Department of Obstetrics and Gynaecology, McMaster University, Hamilton, Ontario, Canada
- Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Endometriosis Research and Treatment, University of California San Diego, San Diego, California, USA
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14
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Lopez-Crisosto C, Arias-Carrasco R, Sepulveda P, Garrido-Olivares L, Maracaja-Coutinho V, Verdejo HE, Castro PF, Lavandero S. Novel molecular insights and public omics data in pulmonary hypertension. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166200. [PMID: 34144090 DOI: 10.1016/j.bbadis.2021.166200] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 06/02/2021] [Accepted: 06/07/2021] [Indexed: 12/21/2022]
Abstract
Pulmonary hypertension is a rare disease with high morbidity and mortality which mainly affects women of reproductive age. Despite recent advances in understanding the pathogenesis of pulmonary hypertension, the high heterogeneity in the presentation of the disease among different patients makes it difficult to make an accurate diagnosis and to apply this knowledge to effective treatments. Therefore, new studies are required to focus on translational and personalized medicine to overcome the lack of specificity and efficacy of current management. Here, we review the majority of public databases storing 'omics' data of pulmonary hypertension studies, from animal models to human patients. Moreover, we review some of the new molecular mechanisms involved in the pathogenesis of pulmonary hypertension, including non-coding RNAs and the application of 'omics' data to understand this pathology, hoping that these new approaches will provide insights to guide the way to personalized diagnosis and treatment.
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Affiliation(s)
- Camila Lopez-Crisosto
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago 8380492, Chile; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8380492, Chile
| | - Raul Arias-Carrasco
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago 8380492, Chile
| | - Pablo Sepulveda
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8380492, Chile; Division of Cardiovascular Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Garrido-Olivares
- Cardiovascular Surgery, Division of Surgery, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Vinicius Maracaja-Coutinho
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago 8380492, Chile
| | - Hugo E Verdejo
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8380492, Chile; Division of Cardiovascular Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo F Castro
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8380492, Chile; Division of Cardiovascular Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago 8380492, Chile; Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
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15
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Zhao M, Wang W, Lu Y, Wang N, Kong D, Shan L. MicroRNA‑153 attenuates hypoxia‑induced excessive proliferation and migration of pulmonary arterial smooth muscle cells by targeting ROCK1 and NFATc3. Mol Med Rep 2021; 23:194. [PMID: 33495839 PMCID: PMC7809904 DOI: 10.3892/mmr.2021.11833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 12/01/2020] [Indexed: 12/20/2022] Open
Abstract
The aim of the present study was to explore the effect of microRNA (miR)‑153 on the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in a hypoxic condition by targeting ρ‑associated, coiled‑coil‑containing protein kinase 1 (ROCK1) and nuclear factor of activated T cells cytoplasmic 3 (NFATc3). The right ventricular systolic pressure, right ventricular hypertrophy index, medial wall thickness and medial wall area were studied at different time‑points after rats were exposed to hypoxia. Western blot analysis was used to detect ROCK1 and NFATc3 protein levels. In addition, reverse transcription‑quantitative (RT‑q) PCR was performed to confirm the mRNA levels of miR‑153, ROCK1 and NFATc3 in human (H)PASMCs under hypoxic conditions. Transfected cells were then used to evaluate the effect of miR‑153 on cell proliferation and migration abilities. The association between miR‑153 and ROCK1 or NFATc3 was identified through double luciferase assays. Hypoxia induced pulmonary vascular remodeling and pulmonary arterial hypertension, which resulted from the abnormal proliferation of HPASMCs. ROCK1 and NFATc3 were the target genes of miR‑153 and miR‑153 mimic inhibited the protein expressions of ROCK1 and NFATc3 in HPASMCs and further inhibited cell proliferation and migration under hypoxic conditions. By contrast, the miR‑153 inhibitor promoted the proliferation and migration of HPASMCs. miR‑153 regulated the proliferation and migration of HPASMCs under hypoxia by targeting ROCK1 and NFATc3.
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Affiliation(s)
- Minjie Zhao
- Department of Respiratory Disease, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Wei Wang
- Department of Respiratory Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Ya Lu
- Department of Respiratory Disease, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Nan Wang
- Department of Respiratory Disease, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Delei Kong
- Department of Respiratory Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Lina Shan
- Department of Respiratory Disease, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
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16
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Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities? Int J Mol Sci 2020; 21:ijms21238901. [PMID: 33255338 PMCID: PMC7727715 DOI: 10.3390/ijms21238901] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022] Open
Abstract
Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients’ quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies.
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