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Zhang RL, Wang WM, Li JQ, Li RW, Zhang J, Wu Y, Liu Y. The role of miR-155 in cardiovascular diseases: Potential diagnostic and therapeutic targets. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2025; 24:200355. [PMID: 39760132 PMCID: PMC11699627 DOI: 10.1016/j.ijcrp.2024.200355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/21/2024] [Accepted: 12/05/2024] [Indexed: 01/07/2025]
Abstract
Cardiovascular diseases (CVDs), such as atherosclerotic cardiovascular diseases, heart failure (HF), and acute coronary syndrome, represent a significant threat to global health and impose considerable socioeconomic burdens. The intricate pathogenesis of CVD involves various regulatory mechanisms, among which microRNAs (miRNAs) have emerged as critical posttranscriptional regulators. In particular, miR-155 has demonstrated differential expression patterns across a spectrum of CVD and is implicated in the etiology and progression of arterial disorders. This systematic review synthesizes current evidence on the multifaceted roles of miR-155 in the modulation of genes and pathological processes associated with CVD. We delineate the potential of miR-155 as a diagnostic biomarker and therapeutic target, highlighting its significant regulatory influence on conditions such as atherosclerosis, aneurysm, hypertension, HF, myocardial hypertrophy, and oxidative stress. Our analysis underscores the transformative potential of miR-155 as a target for intervention in cardiovascular medicine, warranting further investigation into its clinical applicability.
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Affiliation(s)
- Rui-Lin Zhang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Wei-Ming Wang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Ji-Qiang Li
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Run-Wen Li
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Jie Zhang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Ya Wu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yong Liu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
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Wassaifi S, Kaeffer B, Zarrouk S. Cellular Phenotypic Transformation During Atherosclerosis: The Potential Role of miRNAs as Biomarkers. Int J Mol Sci 2025; 26:2083. [PMID: 40076710 PMCID: PMC11900927 DOI: 10.3390/ijms26052083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/01/2024] [Accepted: 07/07/2024] [Indexed: 03/14/2025] Open
Abstract
Cellular phenotypic transformation is a key process that occurs during the development and progression of atherosclerosis. Within the arterial wall, endothelial cells, vascular smooth muscle cells, and macrophages undergo phenotypic changes that contribute to the pathogenesis of atherosclerosis. miRNAs have emerged as potential biomarkers for cellular phenotypic changes during atherosclerosis. Monitoring miR-155-5p, miR-210-3p, and miR-126-3p or 5p levels could provide valuable insights into disease progression, risk of complications, and response to therapeutic interventions. Moreover, miR-92a-3p's elevated levels in atherosclerotic plaques present opportunities for predicting disease progression and related complications. Baseline levels of miR-33a/b hold the potential for predicting responses to cholesterol-lowering therapies, such as statins, and the likelihood of dyslipidemia-related complications. Additionally, the assessment of miR-122-5p levels may offer insights into the efficacy of low-density-lipoprotein-lowering therapies. Understanding the specific miRNA-mediated regulatory mechanisms involved in cellular phenotypic transformations can provide valuable insights into the pathogenesis of atherosclerosis and potentially identify novel therapeutic targets.
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Affiliation(s)
- Souhir Wassaifi
- LR99E10 Human Genetics Laboratory, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Bertrand Kaeffer
- UMR 1280, PhAN, INRAE, Nantes Université, F-44000 Nantes, France;
| | - Sinda Zarrouk
- LR99E10 Human Genetics Laboratory, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
- Institut Pasteur Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
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3
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Euler G, Parahuleva M. Monocytic microRNAs-Novel targets in atherosclerosis therapy. Br J Pharmacol 2025; 182:206-219. [PMID: 38575391 DOI: 10.1111/bph.16367] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/02/2024] [Accepted: 02/16/2024] [Indexed: 04/06/2024] Open
Abstract
Atherosclerosis is a chronic proinflammatory disease of the vascular wall resulting in narrowing of arteries due to plaque formation, thereby causing reduced blood supply that is the leading cause for diverse end-organ damage with high mortality rates. Monocytes/macrophages, activated by elevated circulating lipoproteins, are significantly involved in the formation and development of atherosclerotic plaques. The imbalance between proinflammatory and anti-inflammatory macrophages, arising from dysregulated macrophage polarization, appears to be a driving force in this process. Proatherosclerotic processes acting on monocytes/macrophages include accumulation of cholesterol in macrophages leading to foam cell formation, as well as dysfunctional efferocytosis, all of which contribute to the formation of unstable plaques. In recent years, microRNAs (miRs) were identified as factors that could modulate monocyte/macrophage function and may therefore interfere with the atherosclerotic process. In this review, we present effects of monocyte/macrophage-derived miRs on atherosclerotic processes in order to reveal new treatment options using miRmimics or antagomiRs. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Affiliation(s)
- Gerhild Euler
- Institute of Physiology, Justus Liebig University, Giessen, Germany
| | - Mariana Parahuleva
- Internal Medicine/Cardiology and Angiology, University Hospital of Giessen and Marburg, Marburg, Germany
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4
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Saki N, Haybar H, Maniati M, Davari N, Javan M, Moghimian-Boroujeni B. Modification macrophage to foam cells in atherosclerosis disease: some factors stimulate or inhibit this process. J Diabetes Metab Disord 2024; 23:1687-1697. [PMID: 39610485 PMCID: PMC11599683 DOI: 10.1007/s40200-024-01482-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/16/2024] [Indexed: 11/30/2024]
Abstract
Background Atherosclerosis is an arterial blood vessel disease that begins and progresses by turning macrophages into foam cells. Uptake of oxidized low-density lipoprotein (ox-LDL), cholesterol esterification and cholesterol efflux are the most important factors in the formation of foam cells and play an important role in atherosclerosis. Methods The present study is based on the data obtained from the PubMed database (1961-2024) using the MeSH search terms "Atherosclerosis", "Macrophages" and "Foam cells". Reviews for writing the main text and non-English-language articles were excluded. Result The interaction between ox-LDL and macrophages plays an important role in plaque initiation and promotion processes. Macrophages abnormally digest ox-LDL, resulting in the accumulation of lipids and formation of foam cells. This is an important step in the development of atherosclerosis. Also, several other factors such as inflammatory factors, growth factors, hormones, etc. can play an important role in the development of atherosclerotic lesions or counteract it by affecting the formation of foam cells. Conclusion Several factors can affect the progression of atherosclerosis by affecting macrophage activity or its conversion to foam cells. Also, some of these factors play a protective role against the development and atherosclerosis progression. In this paper, we reviewed some of these factors and their effect on atherosclerosis.
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Affiliation(s)
- Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Habib Haybar
- Cardiology Department, Medical College, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahmood Maniati
- School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nader Davari
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammadreza Javan
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization (IBTO), Tehran, Iran
| | - Bahareh Moghimian-Boroujeni
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
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5
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Wen L, Chen W, Zhu C, Li J, Zhou J, Zhang M, Zhang W, Xue Q. Overexpression of macrophage migration inhibitory factor protects against pressure overload-induced cardiac hypertrophy through regulating the miR-29b-3p/HBP1 axis. Physiol Rep 2024; 12:e16022. [PMID: 38924383 PMCID: PMC11200109 DOI: 10.14814/phy2.16022] [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: 11/07/2023] [Revised: 04/01/2024] [Accepted: 04/01/2024] [Indexed: 06/28/2024] Open
Abstract
Cardiac hypertrophy is an adaptive response to stressors such as high cardiac workload, which might lead to abnormal cardiac function and heart failure. Previous studies have indicated that macrophage migration inhibitory factor (MIF) might play a protective role in cardiac hypertrophy. Here, we aimed to illustrate the mechanism of MIF in protecting against pressure overload-induced cardiac hypertrophy. Transverse aortic constriction (TAC) mouse model was established and we found that overexpression of MIF protected against pressure overload-induced cardiac hypotrophy in TAC treated mice, as evidenced by significantly decreased the heart weight. In addition, transthoracic echocardiography showed that overexpression of MIF restored ejection fraction in TAC-treated mice. While TAC treatment resulted in a much larger cardiomyocyte size in mice, MIF overexpression notably decreased the cardiomyocyte size. Next, we demonstrated that MIF overexpression promoted the expression of miR-29b-3p which further downregulated the expression of its downstream target HMG box protein 1 (HBP1). Overexpression of HBP1 reversed the effect of MIF in alleviating Ang-II induced oxidative stress in cardiomyocytes. In conclusion, our findings suggest that MIF could attenuate pressure overload-induced cardiac hypertrophy through regulating the miR-29b-3p/HBP1 axis.
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Affiliation(s)
- Liang Wen
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Wei Chen
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Cunjun Zhu
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Jie Li
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Juan Zhou
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Minxia Zhang
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Wenqiang Zhang
- Department of CardiologyThe 986th Hospital of Air ForceXi'anShaanxiChina
| | - Qiang Xue
- Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi'anShaanxiChina
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6
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Eshraghi R, Rafiei M, Hadian Jazi Z, Shafie D, Raisi A, Mirzaei H. MicroRNA-155 and exosomal microRNA-155: Small pieces in the cardiovascular diseases puzzle. Pathol Res Pract 2024; 257:155274. [PMID: 38626659 DOI: 10.1016/j.prp.2024.155274] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/18/2024]
Abstract
MicroRNAs (miRs, miRNAs) are known to have a part in various human illnesses, such as those related to the heart. One particular miRNA, miR-155, has been extensively studied and has been found to be involved in hematopoietic lineage differentiation, immunity, viral infections, inflammation, as well as vascular remodeling. These processes have all been connected to cardiovascular diseases, including heart failure, diabetic heart disease, coronary artery disease, and abdominal aortic aneurysm. The impacts of miR-155 depend on the type of cell it is acting on and the specific target genes involved, resulting in different mechanisms of disease. Although, the exact part of miR-155 in cardiovascular illnesses is yet not fully comprehended, as some studies have shown it to promote the development of atherosclerosis while others have shown it to prevent it. As a result, to comprehend the underlying processes of miR-155 in cardiovascular disorders, further thorough study is required. It has been discovered that exosomes that could be absorbed by adjacent or distant cells, control post-transcriptional regulation of gene expression by focusing on mRNA. Exosomal miRNAs have been found to have a range of functions, including participating in inflammatory reactions, cell movement, growth, death, autophagy, as well as epithelial-mesenchymal transition. An increasing amount of research indicates that exosomal miRNAs are important for cardiovascular health and have a major role in the development of a number of cardiovascular disorders, including pulmonary hypertension, atherosclerosis, acute coronary syndrome, heart failure, and myocardial ischemia-reperfusion injury. Herein the role of miR-155 and its exosomal form in heart diseases are summarized.
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Affiliation(s)
- Reza Eshraghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Moein Rafiei
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Hadian Jazi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Davood Shafie
- Cardiology/Heart Failure and Transplantation, Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arash Raisi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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7
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Zhou W, Tang Q, Wang S, Ding L, Chen M, Liu H, Wu Y, Xiong X, Shen Z, Chen W. Local thiamet-G delivery by a thermosensitive hydrogel confers ischemic cardiac repair via myeloid M2-like activation in a STAT6 O-GlcNAcylation-dependent manner. Int Immunopharmacol 2024; 131:111883. [PMID: 38503016 DOI: 10.1016/j.intimp.2024.111883] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/06/2024] [Accepted: 03/13/2024] [Indexed: 03/21/2024]
Abstract
Infarct healing requires a dynamic and orchestrated inflammatory reaction following myocardial infarction (MI). While an uncontrolled excessive inflammatory response exaggerates ischemic injury post-MI, M2-like reparative macrophages may facilitate inflammation regression and promote myocardial healing. However, how protein post-translational modification regulates post-MI cardiac repair and dynamic myeloid activation remains unknown. Here we show that M2-like reparative, but not M1-like inflammatory activation, is enhanced by pharmacologically-induced hyper-O-GlcNAcylation. Mechanistically, myeloid knockdown of O-GlcNAc hydrolase O-GlcNAcase (Oga), which also results in hyper-O-GlcNAcylation, positively regulates M2-like activation in a STAT6-dependent fashion, which is controlled by O-GlcNAcylation of STAT6. Of note, both systemic and local supplementation of thiamet-G (TMG), an Oga inhibitor, effectively facilitates cardiac recovery in mice by elevating the accumulation of M2-like macrophages in infarcted hearts. Our study provides a novel clue for monocyte/macrophage modulating therapies aimed at reducing post-MI hyperinflammation in ischemic myocardium.
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Affiliation(s)
- Wenjing Zhou
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China; School of Life Science, Tianjin University, Tianjin, China
| | - Qingsong Tang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China
| | - Shengnan Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China
| | - Liang Ding
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China
| | - Ming Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China
| | - Hongman Liu
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China; Department of Cardiovascular Medicine, the Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Yong Wu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China
| | - Xiwen Xiong
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China.
| | - Weiqian Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Medical College, Soochow University, Suzhou, China.
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8
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Tan J, Tan YY, Ngian ZK, Chong SY, Rao VK, Wang JW, Zeng X, Ong CT. ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression. iScience 2024; 27:109231. [PMID: 38439966 PMCID: PMC10909902 DOI: 10.1016/j.isci.2024.109231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 12/15/2023] [Accepted: 02/09/2024] [Indexed: 03/06/2024] Open
Abstract
ApoE regulates neurogenesis, although how it influences genetic programs remains elusive. Cortical neurons induced from isogenic control and ApoE-/- human neural stem cells (NSCs) recapitulated key transcriptomic signatures of in vivo counterparts identified from single-cell human midbrain. Surprisingly, ApoE expression in NSC and neural progenitor cells (NPCs) is not required for differentiation. Instead, ApoE prevents the over-proliferation of non-neuronal cells during extended neuronal culture when it is not expressed. Elevated miR-199a-5p level in ApoE-/- cells lowers the EZH1 protein and the repressive H3K27me3 mark, a phenotype rescued by miR-199a-5p steric inhibitor. Reduced H3K27me3 at genes linked to extracellular matrix organization and angiogenesis in ApoE-/- NPC correlates with their aberrant expression and phenotypes in neurons. Interestingly, the ApoE coding sequence, which contains many predicted miR-199a-5p binding sites, can repress miR-199a-5p without translating into protein. This suggests that ApoE maintains neurons integrity through the target-directed miRNA degradation of miR-199a-5p, imparting the H3K27me3-mediated repression of non-neuronal genes during differentiation.
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Affiliation(s)
- Jiazi Tan
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
| | - Yow-Yong Tan
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
| | - Zhen-Kai Ngian
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
| | - Suet-Yen Chong
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Vinay Kumar Rao
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
- Department of Medical Genetics, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India
| | - Jiong-Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117609, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
| | - Xianmin Zeng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
- RxCell Inc, Novato, CA 94945, USA
| | - Chin-Tong Ong
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
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Parsamanesh N, Poudineh M, Siami H, Butler AE, Almahmeed W, Sahebkar A. RNA interference-based therapies for atherosclerosis: Recent advances and future prospects. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 204:1-43. [PMID: 38458734 DOI: 10.1016/bs.pmbts.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.
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Affiliation(s)
- Negin Parsamanesh
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Haleh Siami
- School of Medicine, Islamic Azad University of Medical Science, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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10
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Dahiya N, Kaur M, Singh V. Potential roles of circulatory microRNAs in the onset and progression of renal and cardiac diseases: a focussed review for clinicians. Acta Cardiol 2023; 78:863-877. [PMID: 37318070 DOI: 10.1080/00015385.2023.2221150] [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: 10/29/2022] [Revised: 05/14/2023] [Accepted: 05/30/2023] [Indexed: 06/16/2023]
Abstract
The signalling mechanisms involving the kidney and heart are a niche of networks causing pathological conditions inducing inflammation, reactive oxidative species, cell apoptosis, and organ dysfunction during the onset of clinical complications. The clinical manifestation of the kidney and heart depends on various biochemical processes that influence organ dysfunction coexistence through circulatory networks, which hold utmost importance. The cells of both organs also influence remote communication, and evidence states that it may be explicitly by circulatory small noncoding RNAs, i.e. microRNAs (miRNAs). Recent developments target miRNAs as marker panels for disease diagnosis and prognosis. Circulatory miRNAs expressed in renal and cardiac disease can reveal relevant information about the niche of networks and gene transcription and regulated networks. In this review, we discuss the pertinent roles of identified circulatory miRNAs regulating signal transduction pathways critical in the onset of renal and cardiac disease, which can hold promising future targets for clinical diagnostic and prognostic purposes.
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Affiliation(s)
- Neha Dahiya
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India
| | - Manpreet Kaur
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India
| | - Varsha Singh
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India
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11
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Achmad H, Almajidi YQ, Adel H, Obaid RF, Romero-Parra RM, Kadhum WR, Almulla AF, Alhachami FR, Gabr GA, Mustafa YF, Mahmoudi R, Hosseini-Fard S. The emerging crosstalk between atherosclerosis-related microRNAs and Bermuda triangle of foam cells: Cholesterol influx, trafficking, and efflux. Cell Signal 2023; 106:110632. [PMID: 36805844 DOI: 10.1016/j.cellsig.2023.110632] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/06/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023]
Abstract
In atherosclerosis, the gradual buildup of lipid particles into the sub-endothelium of damaged arteries leads to numerous lipid alterations. The absorption of these modified lipids by monocyte-derived macrophages in the arterial wall leads to cholesterol accumulation and increases the likelihood of foam cell formation and fatty streak, which is an early characteristic of atherosclerosis. Foam cell formation is related to an imbalance in cholesterol influx, trafficking, and efflux. The formation of foam cells is heavily regulated by various mechanisms, among them, the role of epigenetic factors like microRNA alteration in the formation of foam cells has been well studied. Recent studies have focused on the potential interplay between microRNAs and foam cell formation in the pathogenesis of atherosclerosis; nevertheless, there is significant space to progress in this attractive field. This review has focused to examine the underlying processes of foam cell formation and microRNA crosstalk to provide a deep insight into therapeutic implications in atherosclerosis.
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Affiliation(s)
- Harun Achmad
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Indonesia
| | - Yasir Q Almajidi
- Department of Pharmacy, Baghdad College of Medical Sciences, Baghdad, Iraq
| | - Hussein Adel
- Al-Farahidi University, College of Dentistry, Baghdad, Iraq
| | - Rasha Fadhel Obaid
- Department of Biomedical Engineering, Al-Mustaqbal University College, Babylon, Iraq
| | | | - Wesam R Kadhum
- Department of Pharmacy, Kut University College, Kut 52001, Wasit, Iraq
| | - Abbas F Almulla
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Firas Rahi Alhachami
- Radiology Department, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Gamal A Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyedreza Hosseini-Fard
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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12
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Saenz-Pipaon G, Dichek DA. Targeting and delivery of microRNA-targeting antisense oligonucleotides in cardiovascular diseases. Atherosclerosis 2023; 374:44-54. [PMID: 36577600 PMCID: PMC10277317 DOI: 10.1016/j.atherosclerosis.2022.12.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Discovered three decades ago, microRNAs (miRNAs) are now recognized as key players in the pathophysiology of multiple human diseases, including those affecting the cardiovascular system. As such, miRNAs have emerged as promising therapeutic targets for preventing the onset and/or progression of several cardiovascular diseases. Anti-miRNA antisense oligonucleotides or "antagomirs" precisely block the activity of specific miRNAs and are therefore a promising therapeutic strategy to repress pathological miRNAs. In this review, we describe advancements in antisense oligonucleotide chemistry that have significantly improved efficacy and safety. Moreover, we summarize recent approaches for the targeted delivery of antagomirs to cardiovascular tissues, highlighting major advantages as well as limitations of viral (i.e., adenovirus, adeno-associated virus, and lentivirus) and non-viral (i.e., liposomes, extracellular vesicles, and polymer nanoparticles) delivery systems. We discuss recent preclinical studies that use targeted antagomir delivery systems to treat three major cardiovascular diseases (atherosclerosis, myocardial infarction, and cardiac hypertrophy, including hypertrophy caused by hypertension), highlighting therapeutic results and discussing challenges that limit clinical applicability.
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Affiliation(s)
- Goren Saenz-Pipaon
- Department of Medicine, University of Washington School of Medicine, Seattle, USA
| | - David A Dichek
- Department of Medicine, University of Washington School of Medicine, Seattle, USA.
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13
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Oxidative Stress Modulation by ncRNAs and Their Emerging Role as Therapeutic Targets in Atherosclerosis and Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12020262. [PMID: 36829822 PMCID: PMC9952114 DOI: 10.3390/antiox12020262] [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: 12/21/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are pathologies related to ectopic fat accumulation, both of which are continuously increasing in prevalence. These threats are prompting researchers to develop effective therapies for their clinical management. One of the common pathophysiological alterations that underlies both diseases is oxidative stress (OxS), which appears as a result of lipid deposition in affected tissues. However, the molecular mechanisms that lead to OxS generation are different in each disease. Non-coding RNAs (ncRNAs) are RNA transcripts that do not encode proteins and function by regulating gene expression. In recent years, the involvement of ncRNAs in OxS modulation has become more recognized. This review summarizes the most recent advances regarding ncRNA-mediated regulation of OxS in atherosclerosis and NAFLD. In both diseases, ncRNAs can exert pro-oxidant or antioxidant functions by regulating gene targets and even other ncRNAs, positioning them as potential therapeutic targets. Interestingly, both diseases have common altered ncRNAs, suggesting that the same molecule can be targeted simultaneously when both diseases coexist. Finally, since some ncRNAs have already been used as therapeutic agents, their roles as potential drugs for the clinical management of atherosclerosis and NAFLD are analyzed.
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Szydełko J, Matyjaszek-Matuszek B. MicroRNAs as Biomarkers for Coronary Artery Disease Related to Type 2 Diabetes Mellitus-From Pathogenesis to Potential Clinical Application. Int J Mol Sci 2022; 24:ijms24010616. [PMID: 36614057 PMCID: PMC9820734 DOI: 10.3390/ijms24010616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with still growing incidence among adults and young people worldwide. Patients with T2DM are more susceptible to developing coronary artery disease (CAD) than non-diabetic individuals. The currently used diagnostic methods do not ensure the detection of CAD at an early stage. Thus, extensive research on non-invasive, blood-based biomarkers is necessary to avoid life-threatening events. MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that are stable in human body fluids and easily detectable. A number of reports have highlighted that the aberrant expression of miRNAs may impair the diversity of signaling pathways underlying the pathophysiology of atherosclerosis, which is a key player linking T2DM with CAD. The preclinical evidence suggests the atheroprotective and atherogenic influence of miRNAs on every step of T2DM-induced atherogenesis, including endothelial dysfunction, endothelial to mesenchymal transition, macrophage activation, vascular smooth muscle cells proliferation/migration, platelet hyperactivity, and calcification. Among the 122 analyzed miRNAs, 14 top miRNAs appear to be the most consistently dysregulated in T2DM and CAD, whereas 10 miRNAs are altered in T2DM, CAD, and T2DM-CAD patients. This up-to-date overview aims to discuss the role of miRNAs in the development of diabetic CAD, emphasizing their potential clinical usefulness as novel, non-invasive biomarkers and therapeutic targets for T2DM individuals with a predisposition to undergo CAD.
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microRNAs Associated with Carotid Plaque Development and Vulnerability: The Clinician's Perspective. Int J Mol Sci 2022; 23:ijms232415645. [PMID: 36555285 PMCID: PMC9779323 DOI: 10.3390/ijms232415645] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Ischemic stroke (IS) related to atherosclerosis of large arteries is one of the leading causes of mortality and disability in developed countries. Atherosclerotic internal carotid artery stenosis (ICAS) contributes to 20% of all cerebral ischemia cases. Nowadays, atherosclerosis prevention and treatment measures aim at controlling the atherosclerosis risk factors, or at the interventional (surgical or endovascular) management of mature occlusive lesions. There is a definite lack of the established circulating biomarkers which, once modulated, could prevent development of atherosclerosis, and consequently prevent the carotid-artery-related IS. Recent studies emphasize that microRNA (miRNA) are the emerging particles that could potentially play a pivotal role in this approach. There are some research studies on the association between the expression of small non-coding microRNAs with a carotid plaque development and vulnerability. However, the data remain inconsistent. In addition, all major studies on carotid atherosclerotic plaque were conducted on cell culture or animal models; very few were conducted on humans, whereas the accumulating evidence demonstrates that it cannot be automatically extrapolated to processes in humans. Therefore, this paper aims to review the current knowledge on how miRNA participate in the process of carotid plaque formation and rupture, as well as stroke occurrence. We discuss potential target miRNA that could be used as a prognostic or therapeutic tool.
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16
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Chu K, Gu J. microRNA-103a-3p promotes inflammation and fibrosis in nonalcoholic fatty liver disease by targeting HBP1. Immunopharmacol Immunotoxicol 2022; 44:993-1003. [PMID: 35848933 DOI: 10.1080/08923973.2022.2102988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND As a metabolic-associated disease, nonalcoholic fatty liver disease (NAFLD) development is tightly linked to lipid accumulation, inflammatory response, and fibrosis. Our study was intended to expound the role of microRNA (miR)-103a-3p in the pathogenesis of NAFLD. METHODS First, potentially relevant genes in NAFLD were screened using microarray analysis. The expression of lipid metabolism-related, inflammatory, and liver fibrosis indicators in the serum of patients with NAFLD was analyzed. We established a NAFLD mouse model and analyzed the serum level of lipid metabolism- and inflammation-related factors and fibrosis in the liver tissues of NAFLD mice. The targeting relationship between miR-103a-3p and HBP1 was examined by dual-luciferase reporter gene assay, RT-qPCR, and Western blot. Finally, the simultaneous effects of miR-103a-3p and HBP1 knockdown on lipid metabolism, inflammatory response, and liver fibrosis in NAFLD mice were analyzed by rescue experiments. RESULTS MiR-103a-3p was upregulated in the serum of NAFLD patients and liver tissues of NAFLD mice, with increased lipid accumulation, inflammation, and liver fibrosis. HBP1 was reduced in liver tissues of NAFLD mice, and miR-103a-3p bound to and negatively regulated HBP1. Inhibition of miR-103a-3p or promotion of HBP1 improved liver function, decreased lipid accumulation, suppressed inflammatory response, and reduced liver fibrosis in NAFLD mice. Moreover, sh-HBP1 partially reversed the effect of miR-103a-3p inhibitor on NAFLD mice, leading to increased lipid accumulation, elevated inflammation, and fibrosis in the liver of mice. CONCLUSIONS miR-103a-3p inhibits the expression of HBP1, thus suppressing lipid metabolism, stimulating inflammatory responses, and promoting liver fibrosis in NAFLD.
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Affiliation(s)
- Kaifeng Chu
- Department of Hepatology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, P.R. China
| | - Jie Gu
- Department of Gastroenterology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, P.R. China
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17
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Li L, Sun B, Sun Y. Identification of functional TF-miRNA-hub gene regulatory network associated with ovarian endometriosis. Front Genet 2022; 13:998417. [PMID: 36212136 PMCID: PMC9540245 DOI: 10.3389/fgene.2022.998417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Endometriosis (EMs), one of the most common gynecological diseases, seriously affects the health and wellness of women; however, the underlying pathogenesis remains unclear. This study focused on dysregulated genes and their predicted transcription factors (TFs) and miRNAs, which may provide ideas for further mechanistic research. The microarray expression dataset GSE58178, which included six ovarian endometriosis (OE) samples and six control samples, was downloaded from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs). Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to study the cellular and organism-level functions of DEGs. The protein-protein interaction (PPI) network was built and visualized using Cytoscape, and modules and hub genes were explored using various algorithms. Furthermore, we predicted miRNAs and TFs of hub genes using online databases, and constructed the TF-miRNA-hub gene network. There were 124 upregulated genes and 66 downregulated genes in EMs tissues. GO enrichment analysis showed that DEGs were concentrated in reproductive structure development and collagen-containing extracellular matrix, while KEGG pathway analysis showed that glycolysis/gluconeogenesis and central carbon metabolism in cancer require further exploration. Subsequently, HIF1A, LDHA, PGK1, TFRC, and CD9 were identified as hub genes, 22 miRNAs and 34 TFs were predicted to be upstream regulators of hub genes, and these molecules were pooled together. In addition, we found three key feedback loops in the network, MYC-miR-34a-5p-LDHA, YY1-miR-155-5p-HIF1A, and RELA-miR-93-5p-HIF1A, which may be closely related to OE development. Taken together, our study structured a TF-miRNA-hub gene network to decipher the molecular mechanism of OE, which may provide novel insights for clinical diagnosis and treatment.
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Affiliation(s)
- Lu Li
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Sun
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yingpu Sun
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Yingpu Sun,
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18
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Zhang Y, Zhang H, Yang Z, Zhang XH, Miao Q, Li M, Zhai TY, Zheng B, Wen JK. miR-155 down-regulation protects the heart from hypoxic damage by activating fructose metabolism in cardiac fibroblasts. J Adv Res 2022; 39:103-117. [PMID: 35777901 PMCID: PMC9263644 DOI: 10.1016/j.jare.2021.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/15/2021] [Accepted: 10/17/2021] [Indexed: 12/09/2022] Open
Abstract
INTRODUCTION Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury. OBJECTIVES In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs). METHODS Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155-/- and miR-155wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart. RESULTS When both miR-155-/- and miR-155wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart. CONCLUSION In this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.
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Affiliation(s)
- Yu Zhang
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
| | - Hong Zhang
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China; Department of Urology, Second Hospital of Hebei Medical University 050000, China
| | - Zhan Yang
- Department of Urology, Second Hospital of Hebei Medical University 050000, China
| | - Xin-Hua Zhang
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
| | - Qing Miao
- Department of Cardiovascular Medicine, Second Hospital of Hebei Medical University, 050000, China
| | - Min Li
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
| | - Tian-Ying Zhai
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
| | - Bin Zheng
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.
| | - Jin-Kun Wen
- Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.
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Jiang Q, Li Y, Wu Q, Huang L, Xu J, Zeng Q. Pathogenic role of microRNAs in atherosclerotic ischemic stroke: Implications for diagnosis and therapy. Genes Dis 2022; 9:682-696. [PMID: 35782982 PMCID: PMC9243347 DOI: 10.1016/j.gendis.2021.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 12/16/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke resulting from atherosclerosis (particularly in the carotid artery) is one of the major subtypes of stroke and has a high incidence of death. Disordered lipid homeostasis, lipid deposition, local macrophage infiltration, smooth muscle cell proliferation, and plaque rupture are the main pathological processes of atherosclerotic ischemic stroke. Hepatocytes, macrophages, endothelial cells and vascular smooth muscle cells are the main cell types participating in these processes. By inhibiting the expression of the target genes in these cells, microRNAs play a key role in regulating lipid disorders and atherosclerotic ischemic stroke. In this article, we listed the microRNAs implicated in the pathology of atherosclerotic ischemic stroke and aimed to explain their pro- or antiatherosclerotic roles. Our article provides an update on the potential diagnostic use of miRNAs for detecting growing plaques and impending clinical events. Finally, we provide a perspective on the therapeutic use of local microRNA delivery and discuss the challenges for this potential therapy.
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20
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YY1 affects the levels and function of fibulin‑5 in ox‑LDL‑treated vascular smooth muscle cells. Exp Ther Med 2022; 23:407. [PMID: 35619637 PMCID: PMC9115630 DOI: 10.3892/etm.2022.11334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 07/20/2021] [Indexed: 11/27/2022] Open
Abstract
Fibulin-5 is reportedly involved in the pathological process of atherosclerosis (AS) where low expression has been frequently observed in ruptured atherosclerotic plaques. The aim of the present study was to determine the effects of fibulin-5 on the responses of vascular smooth muscle cells (VSMC) to oxidized low-density lipoprotein (ox-LDL). The expression of fibulin-5 was studied in human aortic-VSMCs (HA-VSMCs) treated with ox-LDL. Fibulin-5 was first overexpressed by the transfection of Ov-Fibulin-5 plasmids in HA-VSMCs challenged with ox-LDL to investigate its influence on cell proliferation, migration and invasion using Cell Counting Kit-8, wound healing and Transwell assays. Yin Yang-1 (YY1) was bioinformatically predicted to bind to the promoter sites of fibulin-5, which was subsequently confirmed by dual-luciferase reporter gene assay. Fibulin-5 overexpression was able to suppress cell proliferation, invasion and migration, which was effectively reversed by YY1 silencing by the transfection of siRNA-Fibulin-5 plasmids which could induced fibulin-5 silencing. YY1 binding sites in the promoter region of fibulin-5 were identified and confirmed in vitro by chromatin immunoprecipitation assay and dual-luciferase reporter gene assay. The present results suggested that as a modulator of fibulin-5, YY1 alleviated ox-LDL-induced proliferation, invasion, migration and phenotypic transition from differentiated contractile phenotype to dedifferentiated phenotype in VSMCs. However, the mechanism underlying the YY1-mediated regulation of fibulin-5 expression needs to be confirmed further in vivo. Nevertheless, targeting fibulin-5 and YY1 could be further developed for AS therapy.
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21
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Matz A, Qu L, Karlinsey K, Zhou B. Impact of microRNA Regulated Macrophage Actions on Adipose Tissue Function in Obesity. Cells 2022; 11:1336. [PMID: 35456015 PMCID: PMC9024513 DOI: 10.3390/cells11081336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/12/2022] [Accepted: 04/12/2022] [Indexed: 02/06/2023] Open
Abstract
Obesity-induced adipose tissue dysfunction is bolstered by chronic, low-grade inflammation and impairs systemic metabolic health. Adipose tissue macrophages (ATMs) perpetuate local inflammation but are crucial to adipose tissue homeostasis, exerting heterogeneous, niche-specific functions. Diversified macrophage actions are shaped through finely regulated factors, including microRNAs, which post-transcriptionally alter macrophage activation. Numerous studies have highlighted microRNAs' importance to immune function and potential as inflammation-modulatory. This review summarizes current knowledge of regulatory networks governed by microRNAs in ATMs in white adipose tissue under obesity stress.
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Affiliation(s)
- Alyssa Matz
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
| | - Lili Qu
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
| | - Keaton Karlinsey
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
| | - Beiyan Zhou
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
- Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
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22
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Gui Y, Zheng H, Cao RY. Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms. Front Cardiovasc Med 2022; 9:845942. [PMID: 35498045 PMCID: PMC9043520 DOI: 10.3389/fcvm.2022.845942] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
Foam cells play a vital role in the initiation and development of atherosclerosis. This review aims to summarize the novel insights into the origins, consequences, and molecular mechanisms of foam cells in atherosclerotic plaques. Foam cells are originated from monocytes as well as from vascular smooth muscle cells (VSMC), stem/progenitor cells, and endothelium cells. Novel technologies including lineage tracing and single-cell RNA sequencing (scRNA-seq) have revolutionized our understanding of subtypes of monocyte- and VSMC-derived foam cells. By using scRNA-seq, three main clusters including resident-like, inflammatory, and triggering receptor expressed on myeloid cells-2 (Trem2 hi ) are identified as the major subtypes of monocyte-derived foam cells in atherosclerotic plaques. Foam cells undergo diverse pathways of programmed cell death including apoptosis, autophagy, necroptosis, and pyroptosis, contributing to the necrotic cores of atherosclerotic plaques. The formation of foam cells is affected by cholesterol uptake, efflux, and esterification. Novel mechanisms including nuclear receptors, non-coding RNAs, and gut microbiota have been discovered and investigated. Although the heterogeneity of monocytes and the complexity of non-coding RNAs make obstacles for targeting foam cells, further in-depth research and therapeutic exploration are needed for the better management of atherosclerosis.
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Affiliation(s)
- Yuzhou Gui
- Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Phase I Clinical Research and Quality Consistency Evaluation for Drugs, Shanghai, China
| | - Hongchao Zheng
- Department of Cardiovascular, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
| | - Richard Y. Cao
- Department of Cardiovascular, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
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23
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Li H, Zhan J, Chen C, Wang D. MicroRNAs in cardiovascular diseases. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:140-168. [PMID: 37724243 PMCID: PMC10471109 DOI: 10.1515/mr-2021-0001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 12/29/2021] [Indexed: 09/20/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death and disability worldwide, despite the wide diversity of molecular targets identified and the development of therapeutic methods. MicroRNAs (miRNAs) are a class of small (about 22 nucleotides) non-coding RNAs (ncRNAs) that negatively regulate gene expression at the post-transcriptional level in the cytoplasm and play complicated roles in different CVDs. While miRNA overexpression in one type of cell protects against heart disease, it promotes cardiac dysfunction in another type of cardiac cell. Moreover, recent studies have shown that, apart from cytosolic miRNAs, subcellular miRNAs such as mitochondria- and nucleus-localized miRNAs are dysregulated in CVDs. However, the functional properties of cellular- and subcellular-localized miRNAs have not been well characterized. In this review article, by carefully revisiting animal-based miRNA studies in CVDs, we will address the regulation and functional properties of miRNAs in various CVDs. Specifically, the cell-cell crosstalk and subcellular perspective of miRNAs are highlighted. We will provide the background for attractive molecular targets that might be useful in preventing the progression of CVDs and heart failure (HF) as well as insights for future studies.
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Affiliation(s)
- Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Jiabing Zhan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Daowen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
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24
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Mahmoudi A, Moadab F, Safdarian E, Navashenaq JG, Rezaee M, Gheibihayat SM. MicroRNAs and Efferocytosis: Implications for Diagnosis and Therapy. Mini Rev Med Chem 2022; 22:2641-2660. [PMID: 35362375 DOI: 10.2174/1389557522666220330150937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/24/2021] [Accepted: 01/19/2022] [Indexed: 11/22/2022]
Abstract
About 10-100 billion cells are generated in the human body in a day, and accordingly, 10-100 billion cells predominantly die for maintaining homeostasis. Dead cells generated by apoptosis are also rapidly engulfed by macrophages (Mθs) to be degraded. In case of the inefficient engulfment of apoptotic cells (ACs) via Mθs, they experience secondary necrosis and thus release intracellular materials, which display damage-associated molecular patterns (DAMPs) and result in diseases. Over the last decades, researchers have also reflected on the significant contribution of microRNAs (miRNAs) to autoimmune diseases through the regulation of Mθs functions. Moreover, miRNAs have shown intricate involvement with completely adjusting basic Mθs functions, such as phagocytosis, inflammation, efferocytosis, tumor promotion, and tissue repair. In this review, the mechanism of efferocytosis containing "Find-Me", "Eat-Me", and "Digest-Me" signals is summarized and the biogenesis of miRNAs is briefly described. Finally, the role of miRNAs in efferocytosis is discussed. It is concluded that miRNAs represent promising treatments and diagnostic targets in impaired phagocytic clearance, which leads to different diseases.
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Affiliation(s)
- Ali Mahmoudi
- Department of medical biotechnology and nanotechnology, faculty of medicine, Mashhad University of Medical science, Iran
| | - Fatemeh Moadab
- Medical student, Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Esmat Safdarian
- Legal Medicine Research Center, Legal Medicine Organization, Tehran Iran
| | | | - Mehdi Rezaee
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran;
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Vascular Pathobiology: Atherosclerosis and Large Vessel Disease. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00006-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Petković A, Erceg S, Munjas J, Ninić A, Sopić M. Circulating non-coding RNAs as biomarkers in coronary artery disease. ARHIV ZA FARMACIJU 2022. [DOI: 10.5937/arhfarm72-36166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Coronary artery disease (CAD) is a leading cause of mortality worldwide. Atherosclerosis involves an interplay of different pathological mechanisms, such as progressive inflammation, abnormal lipid metabolism, and oxidative stress, and as such represents the basic pathological phenomenon underlying CAD. Atherosclerotic plaque narrows the lumen of coronary arteries, creating an ischemic environment for the heart muscle, which finally leads to clinical complications, such as acute myocardial infarction. Currently, there are no biomarkers that could predict plaque stability or major adverse cardiovascular events (MACE). Numerous functional non-coding RNA (ncRNA) species influence basic cellular functions, and as such play a role in the development and progression of CAD. Of these ncRNAs, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. Considering that ncRNAs detected in extracellular fluids can originate from different cells, circulating ncRNAs are being intensively investigated as potential biomarkers in the diagnosis and prognosis of CAD. In the following paper, we provide current insights into potential molecular mechanisms by which miRNAs and lncRNAs contribute to the pathology of CAD and discuss their potential role as biomarkers in diagnosis and prognosis of disease.
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Chang YJ, Wang KC. Therapeutic perspectives of extracellular vesicles and extracellular microRNAs in atherosclerosis. CURRENT TOPICS IN MEMBRANES 2021; 87:255-277. [PMID: 34696887 DOI: 10.1016/bs.ctm.2021.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Extracellular signaling molecules, such as growth factors, cytokines, and hormones, regulate cell behaviors and fate through endocrine, paracrine, and autocrine actions and play essential roles in maintaining tissue homeostasis. MicroRNAs, an important class of posttranscriptional modulators, could stably present in extracellular space and body fluids and participate in intercellular communication in health and diseases. Indeed, recent studies demonstrated that microRNAs could be secreted through vesicular and non-vesicular routes, transported in body fluids, and then transmitted to recipient cells to regulate target gene expression and signaling events. Over the past decade, a great deal of effort has been made to investigate the functional roles of extracellular vesicles and extracellular microRNAs in pathological conditions. Emerging evidence suggests that altered levels of extracellular vesicles and extracellular microRNAs in body fluids, as part of the cellular responses to atherogenic factors, are associated with the development of atherosclerosis. This review article provides a brief overview of extracellular vesicles and perspectives of their applications as therapeutic tools for cardiovascular pathologies. In addition, we highlight the role of extracellular microRNAs in atherogenesis and offer a summary of circulating microRNAs in liquid biopsies associated with atherosclerosis.
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Affiliation(s)
- Ya-Ju Chang
- Department of Family Medicine and Public Health, School of Medicine, University of California San Diego, La Jolla, CA, United States
| | - Kuei-Chun Wang
- School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, United States.
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Rachmawati E, Sargowo D, Rohman MS, Widodo N, Kalsum U. miR-155-5p predictive role to decelerate foam cell atherosclerosis through CD36, VAV3, and SOCS1 pathway. Noncoding RNA Res 2021; 6:59-69. [PMID: 33869908 PMCID: PMC8027696 DOI: 10.1016/j.ncrna.2021.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/14/2021] [Indexed: 01/22/2023] Open
Abstract
MicroRNAs (miRNAs) are noncoding RNA molecules that play a significant role in atherosclerosis pathogenesis through post-transcriptional regulation. In the present work, a bioinformatic analysis using TargetScan and miRdB databases was performed to identify the miRNAs targeting three genes involved in foam cell atherosclerosis (CD36, Vav3, and SOCS1). A total number of three hundred and sixty-seven miRNAs were recognized and only miR-155-5p was selected for further evaluation based on Venn analysis. Another objective of this study was to evaluate the biological process and regulatory network of miR-155-5p associated with foam cell atherosclerosis using DIANA, DAVID, Cytoscape, and STRING tools. Additionally, the comprehensive literature review was performed to prove the miR-155-5p function in foam cell atherosclerosis. miR-155-5p might be related with ox-LDL uptake and endocytosis in macrophage cell by targeting CD36 and Vav3 genes which was showed from the KEGG pathways hsa04979, hsa04666, hsa04145 H, hsa04810, and GO:0099632, GO:0060100, GO:0010743, GO:001745. Furthermore, miR-155-5p was also predicted to increase the cholesterol efflux from macrophage by inhibit SOCS1 expression based on KEGG pathway hsa04120. Eleven original studies were included in the review and strongly suggest the role of miR-155-5p in foam cell atherosclerosis inhibition.
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Affiliation(s)
- Ermin Rachmawati
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
- Faculty of Medicine and Health Sciences UIN Maulana Malik Ibrahim Malang
| | - Djanggan Sargowo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - M. Saifur Rohman
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
- Brawijaya Cardiovascular Research Center
| | - Nashi Widodo
- Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Brawijaya, Malang, Indonesia
| | - Umi Kalsum
- Department of Pharmacology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
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Li N, Ouyang Y, Xu X, Yuan Z, Liu C, Zhu Z. MiR-155 promotes colitis-associated intestinal fibrosis by targeting HBP1/Wnt/β-catenin signalling pathway. J Cell Mol Med 2021; 25:4765-4775. [PMID: 33769664 PMCID: PMC8107084 DOI: 10.1111/jcmm.16445] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
Intestinal fibrosis is the most common complication of Crohn's disease (CD) that is one major disorder of inflammatory bowel disease (IBD), but the precise mechanism remains unclear. MiR-155 has been involved in fibrotic diseases. Here, we determined the role of miR-155 in regulating intestinal fibrosis. MiR-155 levels were significantly up-regulated in CD patients with intestinal stricture CD. The overexpression of miR-155 significantly aggravated TNBS-induced CD-associated intestinal fibrosis. Mechanistically, we identified that HBP1, a negative regulator of the Wnt/β-catenin signalling pathway, is a direct target of miR-155. Moreover, in vitro and in vivo experiments suggested that the miR-155/HBP1 axis activates Wnt/β-catenin signalling pathway to induce intestinal fibrosis. Taken together, we demonstrated that miR-155 directly targets HBP1 to induce CD-associated intestinal fibrosis via Wnt/β-catenin signalling pathway.
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Affiliation(s)
- Nianshuang Li
- Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Digestive DiseaseThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yaobin Ouyang
- Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xinbo Xu
- Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Zhenxiang Yuan
- Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Chunquan Liu
- Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Zhenhua Zhu
- Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Digestive DiseaseThe First Affiliated Hospital of Nanchang UniversityNanchangChina
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Adly Sadik N, Ahmed Rashed L, Ahmed Abd-El Mawla M. Circulating miR-155 and JAK2/STAT3 Axis in Acute Ischemic Stroke Patients and Its Relation to Post-Ischemic Inflammation and Associated Ischemic Stroke Risk Factors. Int J Gen Med 2021; 14:1469-1484. [PMID: 33911894 PMCID: PMC8071708 DOI: 10.2147/ijgm.s295939] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Background “Micro RNAs and their target genes recently have been identified to play a crucial role in the molecular pathogenesis of post-stroke ischemic cellular injury, which elucidates their new role in ischemic stroke diagnosis and therapy”. Thus, we evaluated the relative serum expression of miR-155, an inflammatory micro RNA, and the mRNAs (JAK2/STAT3) in acute ischemic stroke patients and its associations with the inflammatory cytokine TNF-α and different stroke risk factors. Subjects and Methods The relative expression of serum miR-155 and mRNAs (JAK2/STAT3) was assessed using RT-PCR, serum TNF-α was measured using ELIZA in 46 acute ischemic stroke patients and 50 control subjects. Receiver operating characteristic (ROC) curve was constructed to assess the specificity and sensitivity of circulating miR-155, JAK2/STAT3 as biomarkers for acute ischemic stroke. Results Circulating miR-155, JAK2/STAT3 were significantly up-regulated among stroke patients (8.5, 2.9, 4.2 fold respectively, P<0.001) with significant increase in TNF-α (263.8 ± 10.7 pg/mL, P <0.001). MiR-155, JAK2/STAT3 were positively correlated with TNF-α. MiR-155, JAK2/STAT3 were significantly increased in stroke patients and associated with risk factors such as hypertension, carotid atherosclerosis, and atrial fibrillation. Our study revealed that miR-155 has diagnostic accuracy for acute ischemic stroke where AUC=0.9, (P<0.001). Conclusion The elevated expressions of circulating miR-155, JAK2/STAT3, and TNF-α in acute ischemic stroke patients could trigger post-stroke cellular inflammation. MiR-155 could be used as potential inflammatory biomarker for acute ischemic stroke. However, further clinical studies are still needed to determine the exact role of miRNAs and different signal transduction expressions in the stage of acute ischemic stroke.
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Affiliation(s)
- Noha Adly Sadik
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila Ahmed Rashed
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Javadifar A, Rastgoo S, Banach M, Jamialahmadi T, Johnston TP, Sahebkar A. Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs. Int J Mol Sci 2021; 22:2529. [PMID: 33802600 PMCID: PMC7961492 DOI: 10.3390/ijms22052529] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/24/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.
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Affiliation(s)
- Amin Javadifar
- Department of Allergy and Immunology, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; (A.J.); (S.R.)
| | - Sahar Rastgoo
- Department of Allergy and Immunology, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; (A.J.); (S.R.)
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, 93338 Lodz, Poland
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI), 93338 Lodz, Poland
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan 9479176135, Iran;
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
| | - Thomas P. Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108-2718, USA;
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948954, Iran
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
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Citrin KM, Fernández-Hernando C, Suárez Y. MicroRNA regulation of cholesterol metabolism. Ann N Y Acad Sci 2021; 1495:55-77. [PMID: 33521946 DOI: 10.1111/nyas.14566] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/27/2020] [Accepted: 01/09/2021] [Indexed: 12/17/2022]
Abstract
MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Since many microRNAs have multiple mRNA targets, they are uniquely positioned to regulate the expression of several molecules and pathways simultaneously. For example, the multiple stages of cholesterol metabolism are heavily influenced by microRNA activity. Understanding the scope of microRNAs that control this pathway is highly relevant to diseases of perturbed cholesterol metabolism, most notably cardiovascular disease (CVD). Atherosclerosis is a common cause of CVD that involves inflammation and the accumulation of cholesterol-laden cells in the arterial wall. However, several different cell types participate in atherosclerosis, and perturbations in cholesterol homeostasis may have unique effects on the specialized functions of these various cell types. Therefore, our review discusses the current knowledge of microRNA-mediated control of cholesterol homeostasis, followed by speculation as to how these microRNA-mRNA target interactions might have distinctive effects on different cell types that participate in atherosclerosis.
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Affiliation(s)
- Kathryn M Citrin
- Department of Comparative Medicine and Department of Pathology, Integrative Cell Signaling and Neurobiology of Metabolism Program, and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut.,Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
| | - Carlos Fernández-Hernando
- Department of Comparative Medicine and Department of Pathology, Integrative Cell Signaling and Neurobiology of Metabolism Program, and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut
| | - Yajaira Suárez
- Department of Comparative Medicine and Department of Pathology, Integrative Cell Signaling and Neurobiology of Metabolism Program, and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut
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Implications for MicroRNA involvement in the prognosis and treatment of atherosclerosis. Mol Cell Biochem 2021; 476:1327-1336. [PMID: 33389489 DOI: 10.1007/s11010-020-03992-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 11/16/2020] [Indexed: 12/30/2022]
Abstract
MicroRNAs (miRNAs) are important molecules which implicated in various processes, such as differentiation, development, cell survival, cell apoptosis and also cell metabolism. Investigations over decades have revealed that various genes and signaling pathways are implicated in beginning and development of atherosclerosis, several miRNAs being involved in these dysregulated genes and pathways. miRNAs have provided new molecular vision in the context of atherosclerosis. miRNAs are considered as important regulators of cellular migration, differentiation, proliferation, lipid uptake and efflux, as well as cytokine production. Application of miRNAs as a biomarker in diagnosis, prognosis and even therapy is quiet exciting. Although animal researches showed promising results, still some practical difficulties and technical challenges need to be addressed before translation from researches into clinical practices. In this review, we present important data about three critical cells endothelial cell (EC), vascular smooth muscle cell (VSMC), and monocyte/macrophage and regulation of these cells through miRNAs. Furthermore, we discuss about the potential of miRNAs as a prognostic and diagnostic biomarkers, therapeutic opportunities and challenges, and also future perspective.
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Majid M, Masood A, Masoodi SR, Naykoo NA, Shah IA, Nissar B, Khan NS, ul Afshan F, Ganai BA. Expression analysis of microRNA-155 in type 2 diabetes in Kashmiri population. Int J Diabetes Dev Ctries 2020. [DOI: 10.1007/s13410-020-00840-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Fazmin IT, Achercouk Z, Edling CE, Said A, Jeevaratnam K. Circulating microRNA as a Biomarker for Coronary Artery Disease. Biomolecules 2020; 10:E1354. [PMID: 32977454 PMCID: PMC7598281 DOI: 10.3390/biom10101354] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/15/2020] [Accepted: 09/19/2020] [Indexed: 12/14/2022] Open
Abstract
Coronary artery disease (CAD) is the leading cause of sudden cardiac death in adults, and new methods of predicting disease and risk-stratifying patients will help guide intervention in order to reduce this burden. Current CAD detection involves multiple modalities, but the consideration of other biomarkers will help improve reliability. The aim of this narrative review is to help researchers and clinicians appreciate the growing relevance of miRNA in CAD and its potential as a biomarker, and also to suggest useful miRNA that may be targets for future study. We sourced information from several databases, namely PubMed, Scopus, and Google Scholar, when collating evidentiary information. MicroRNAs (miRNA) are short, noncoding RNAs that are relevant in cardiovascular physiology and pathophysiology, playing roles in cardiac hypertrophy, maintenance of vascular tone, and responses to vascular injury. CAD is associated with changes in miRNA expression profiles, and so are its risk factors, such as abnormal lipid metabolism and inflammation. Thus, they may potentially be biomarkers of CAD. Nevertheless, there are limitations in using miRNA. These include cost and the presence of several confounding factors that may affect miRNA profiles. Furthermore, there is difficulty in the normalisation of miRNA values between published studies, due to pre-analytical variations in samples.
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Affiliation(s)
- Ibrahim T. Fazmin
- Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7AL, UK; (I.T.F.); (Z.A.); (C.E.E.)
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK
| | - Zakaria Achercouk
- Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7AL, UK; (I.T.F.); (Z.A.); (C.E.E.)
| | - Charlotte E. Edling
- Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7AL, UK; (I.T.F.); (Z.A.); (C.E.E.)
| | - Asri Said
- School of Medicine, University Malaysia Sarawak, Kota Samarahan 94300, Sarawak, Malaysia;
| | - Kamalan Jeevaratnam
- Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7AL, UK; (I.T.F.); (Z.A.); (C.E.E.)
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Zareba L, Fitas A, Wolska M, Junger E, Eyileten C, Wicik Z, De Rosa S, Siller-Matula JM, Postula M. MicroRNAs and Long Noncoding RNAs in Coronary Artery Disease: New and Potential Therapeutic Targets. Cardiol Clin 2020; 38:601-617. [PMID: 33036721 DOI: 10.1016/j.ccl.2020.07.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Noncoding RNAs (ncRNAs), including long noncoding RNAs and microRNAs, play an important role in coronary artery disease onset and progression. The ability of ncRNAs to simultaneously regulate many target genes allows them to modulate various key processes involved in atherosclerosis, including lipid metabolism, smooth muscle cell proliferation, autophagy, and foam cell formation. This review focuses on the therapeutic potential of the most important ncRNAs in coronary artery disease. Moreover, various other promising microRNAs and long noncoding RNAs that attract substantial scientific interest as potential therapeutic targets in coronary artery disease and merit further investigation are presented.
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Affiliation(s)
- Lukasz Zareba
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland
| | - Alex Fitas
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland
| | - Marta Wolska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland
| | - Eva Junger
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland
| | - Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland; Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Alameda da Universidade, s/n-Anchieta, São Paulo 09606-045, Brazil
| | - Salvatore De Rosa
- Division of Cardiology, Department of Medical and Surgical Sciences, "Magna Graecia" University, Viale Europa, Catanzaro 88100, Italy
| | - Jolanta M Siller-Matula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Spitalgasse 23, Vienna 1090, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., Warsaw 02-097, Poland; Longevity Center, Warsaw, Poland.
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Lightbody RJ, Taylor JMW, Dempsie Y, Graham A. MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis. World J Cardiol 2020; 12:303-333. [PMID: 32843934 PMCID: PMC7415235 DOI: 10.4330/wjc.v12.i7.303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/03/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Accumulation of macrophage “foam” cells, laden with cholesterol and cholesteryl ester, within the intima of large arteries, is a hallmark of early “fatty streak” lesions which can progress to complex, multicellular atheromatous plaques, involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response. Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway. Within the arterial intima, however, this mechanism is overwhelmed, leading to distinct changes in macrophage phenotype and inflammatory status. Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function, and in particular the importance of small non-coding micro-RNA (miRNA) sequences in this context. This review identifies some of the miRNA sequences which play a key role in regulating “foam” cell formation and atherogenesis, highlighting sequences involved in cholesterol accumulation, those influencing inflammation in sterol-loaded cells, and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.
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Affiliation(s)
- Richard James Lightbody
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Janice Marie Walsh Taylor
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Yvonne Dempsie
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Annette Graham
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
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The Interplay between Oxidative Stress and miRNAs in Obesity-Associated Hepatic and Vascular Complications. Antioxidants (Basel) 2020; 9:antiox9070607. [PMID: 32664383 PMCID: PMC7402144 DOI: 10.3390/antiox9070607] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/02/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Nowadays, the obesity pandemic is one of the most relevant health issues worldwide. This condition is tightly related to comorbidities such as non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs), namely atherosclerosis. Dysregulated lipid metabolism and inflammation link these three diseases, leading to a subsequent increase of oxidative stress (OS) causing severe cellular damage. On the other hand, microRNAs (miRNAs) are short, single-stranded, non-coding RNAs that act as post-transcriptional negative regulators of gene expression, thus being involved in the molecular mechanisms that promote the development of many pathologies including obesity and its comorbidities. The involvement of miRNAs in promoting or opposing OS in disease progression is becoming more evident. Some miRNAs, such as miR-200a and miR.421, seem to play important roles in OS control in NAFLD. On the other hand, miR-92a and miR-133, among others, are important in the development of atherosclerosis. Moreover, since both diseases are linked to obesity, they share common altered miRNAs, being miR-34a and miR-21 related to OS. This review summarizes the latest advances in the knowledge about the mechanisms of oxidative stress (OS) generation in obesity-associated NAFLD and atherosclerosis, as well as the role played by miRNAs in the regulation of such mechanisms.
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Zheng J, Wang W, Hong T, Yang S, Shen J, Liu C. Suppression of microRNA-155 exerts an anti-inflammatory effect on CD4+ T cell-mediated inflammatory response in the pathogenesis of atherosclerosis. Acta Biochim Biophys Sin (Shanghai) 2020; 52:654-664. [PMID: 32372074 DOI: 10.1093/abbs/gmaa040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/27/2022] Open
Abstract
In the current study, we aimed to investigate the effects of miR-155 on CD4+ T cell-mediated immune response in the pathogenesis of atherosclerosis. CD34+ hematopoietic stem cells, CD4+ T lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) were harvested from the same donor. Knockdown of miR-155 in the CD4+ T cells was achieved by lentiviral transfection, whereas control RNA-transfected or untransfected lymphocytes were used as controls. The transfected CD4+ T cells were activated by incubating with oxidized low-density lipoprotein-treated dendritic cells. The proliferative capacities, phenotype distribution, and cytokine secretion profiles of the activated CD4+ T cells from different groups were evaluated. The activated lymphocytes were used to treat ECs co-cultivated with VSMCs. The ability of the CD4+ T cells to induce the apoptosis of the ECs and to promote the proliferation of the VSMCs was investigated. Inhibition of miR-155 was found to significantly reduce the proliferation rate of the transfected CD4+ T cells. CD4+ T lymphocytes transfected with the miR-155 inhibitor showed increased populations of T helper type 2 and regulatory T cells, as well as more production of anti-inflammatory cytokines. MiR-155 knockdown was also shown to significantly hamper the ability to CD4+ T cells to induce EC apoptosis and to promote the growth of VSMCs. Our data suggested that inhibition of miR-155 in CD4+ T cells could slow down the formation of atherosclerotic plaques. These results lay the groundwork for future research on the therapeutic potential of miR-155 against atherosclerosis-associated cardiovascular diseases.
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Affiliation(s)
- Jiayu Zheng
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenshuo Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Tao Hong
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shouguo Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jinqiang Shen
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chen Liu
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Jia Y, Wei Y. Modulators of MicroRNA Function in the Immune System. Int J Mol Sci 2020; 21:E2357. [PMID: 32235299 PMCID: PMC7177468 DOI: 10.3390/ijms21072357] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/23/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) play a key role in fine-tuning host immune homeostasis and responses through the negative regulation of mRNA stability and translation. The pathways regulated by miRNAs are well characterized, but the precise mechanisms that control the miRNA-mediated regulation of gene expression during immune cell-development and immune responses to invading pathogens are incompletely understood. Context-specific interactions of miRNAs with other RNA species or proteins may modulate the function of a given miRNA. Dysregulation of miRNA function is associated with various human diseases, such as cardiovascular diseases and cancers. Here, we review the potential modulators of miRNA function in the immune system, including the transcription regulators of miRNA genes, miRNA-processing enzymes, factors affecting miRNA targeting, and intercellular communication.
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Affiliation(s)
- Yunhui Jia
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yuanyuan Wei
- Department of Immunology, Shanghai Key laboratory of Bioactive Small Molecules, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Ghadrdoost B, Aboutaleb N, Nikougoftar Zarif M, Nakhlestani M, Haghjoo M, Sameie S. Association between cytokines and two circulating micro-RNAs and development of premature ventricular contractions-induced cardiomyopathy. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 22:1125-1131. [PMID: 31998452 PMCID: PMC6885395 DOI: 10.22038/ijbms.2019.36362.8662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Objective(s): Recent progress in understanding the pathogenesis of premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) has suggested a key role for inflammation. The aim of this study was to evaluate the expression of messenger RNAs (mRNAs) and the protein production of interleukin-6 (IL-6), IL-10, tumor necrosis factor alpha (TNF-α) and interferon-γ (IFN-γ) and two circulating micro-RNAs related to inflammation and cardiovascular disease; miR-155 and miR-146. Materials and Methods: The study population was comprised 25 patients with PIC and 25 patients with normal left ventricular ejection fraction despite frequent PVCs. TNF-α, IL-6, IL10, and IFN-γ levels were evaluated in peripheral blood mononuclear cells (PBMCs) by flow cytometry and their mRNAs were assessed by real time PCR. We analyzed circulating levels of these cytokines by enzyme linked immunosorbent assay (ELISA). Two circulating micro-RNAs, miR-155 and miR-146a, were also investigated. Results: The flow cytometry findings showed that the median fluorescence intensity (MFI) of antibodies reacted with the IL-6 and TNF-α were higher in PIC group than the control group (P-value<0.001). In ELISA, the levels of IL-6 (P-value<0.001) and TNF-α (P-value <0.001) and in RT-PCR the relative expression levels of IL-6 (P-value<0.001) and TNF-α (P-value<0.001) were significantly higher in the PIC group. The relative expression levels of miR-155 and miR-146a were not significantly different between 2 groups (P-value>0.05). Conclusion: In our patients with PIC, there was an elevation in the expression levels of IL-6 and TNF-α in PBMCs. This finding may provide further insights into the inflammatory pathways involved in PIC.
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Affiliation(s)
- Behshid Ghadrdoost
- Physiology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nahid Aboutaleb
- Physiology Research Center, Physiology Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahin Nikougoftar Zarif
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mojdeh Nakhlestani
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Majid Haghjoo
- Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shahram Sameie
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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Shoeibi S. Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis. Acta Physiol (Oxf) 2020; 228:e13353. [PMID: 31344321 DOI: 10.1111/apha.13353] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are a group of small single strand and noncoding RNAs that regulate several physiological and molecular signalling pathways. Alterations of miRNA expression profiles may be involved with pathophysiological processes underlying the development of atherosclerosis and cardiovascular diseases, including changes in the functions of the endothelial cells and vascular smooth muscle cells, such as cell proliferation, migration and inflammation, which are involved in angiogenesis, macrophage function and foam cell formation. Thus, miRNAs can be considered to have a crucial role in the progression, modulation and regulation of every stage of atherosclerosis. Such potential biomarkers will enable us to predict therapeutic response and prognosis of cardiovascular diseases and adopt effective preclinical and clinical treatment strategies. In the present review article, the current data regarding the role of miRNAs in atherosclerosis were summarized and the potential miRNAs as prognostic, diagnostic and theranostic biomarkers in preclinical and clinical studies were further discussed. The highlights of this review are expected to present opportunities for future research of clinical therapeutic approaches in vascular diseases resulting from atherosclerosis with an emphasis on miRNAs.
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Affiliation(s)
- Sara Shoeibi
- Atherosclerosis Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
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Oggero S, Austin-Williams S, Norling LV. The Contrasting Role of Extracellular Vesicles in Vascular Inflammation and Tissue Repair. Front Pharmacol 2019; 10:1479. [PMID: 31920664 PMCID: PMC6928593 DOI: 10.3389/fphar.2019.01479] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/13/2019] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles are a heterogeneous family of vesicles, generated from different subcellular compartments and released into the extracellular space. Composed of a lipid bilayer encompassing both soluble cytosolic material and nuclear components, these organelles have been recently described as novel regulators of intercellular communication between adjacent and remote cells. Due to their diversified composition and biological content, they portray specific signatures of cellular activation and pathological processes, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Circulating vesicles, especially those released from platelets, leukocytes, and endothelial cells are found to play a critical role in activating several fundamental cells within the vasculature, including endothelial cells and vascular smooth muscle cells. Their intrinsic activity and immunomodulatory properties lends them to not only promote vascular inflammation, but also enhance tissue regeneration, vascular repair, and indeed resolution. In this review we aim to recapitulate the recent findings concerning the roles played by EVs that originate from different circulating cells, with particular reference to their action on the endothelium. We focus herein, on the interaction of platelet and leukocyte EVs with the endothelium. In addition, their potential biological function in promoting tissue resolution and vascular repair will also be discussed.
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Affiliation(s)
- Silvia Oggero
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Shani Austin-Williams
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Lucy Victoria Norling
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
- Centre for Inflammation and Therapeutic Innovation Queen Mary University of London, London, United Kingdom
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44
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MicroRNAs as the actors in the atherosclerosis scenario. J Physiol Biochem 2019; 76:1-12. [PMID: 31808077 DOI: 10.1007/s13105-019-00710-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is considered as the most common cardiovascular disease and a leading cause of global mortality, which develops through consecutive steps. Various cellular and molecular biomarkers such as microRNAs are identified to be involved in atherosclerosis progression. MicroRNAs are a group of endogenous, short, non-coding RNAs, which are able to bind to specific sequences on target messenger RNAs and thereby modulate gene expression post-transcriptionally. MicroRNAs are key players in wide range of biological processes; thus, their expression level is regulated in pathophysiological conditions. Ample evidences including in vitro and in vivo studies approved a critical role of microRNAs in epigenetic and the sequential processes of atherosclerosis from risk factors to plaque formation, progression, and rupture. Based on these findings, miRNAs seems to be promising candidates for therapeutic approach. This review summarizes the role of miRNAs in atherosclerosis development, epigenetic, and therapy. Moreover, the application of exosomes in miRNA delivery, and/or their prognostic and diagnostic values are also discussed.
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van der Laan SW, Siemelink MA, Haitjema S, Foroughi Asl H, Perisic L, Mokry M, van Setten J, Malik R, Dichgans M, Worrall BB, Samani NJ, Schunkert H, Erdmann J, Hedin U, Paulsson-Berne G, Björkegrenn JLM, de Borst GJ, Asselbergs FW, den Ruijter FW, de Bakker PIW, Pasterkamp G. Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 11:e002115. [PMID: 30354329 PMCID: PMC7664607 DOI: 10.1161/circgen.118.002115] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Supplemental Digital Content is available in the text. Background: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms. Methods: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression. Results: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10−6 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood. Conclusions: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics.
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Affiliation(s)
- Sander W van der Laan
- Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (S.W.v.d.L., M.A.S., S.H., H.M.d.R., G.P.)
| | - Marten A Siemelink
- Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (S.W.v.d.L., M.A.S., S.H., H.M.d.R., G.P.).,Department of Clinical Genetics, University Medical Center Utrecht, University Utrecht, The Netherlands (M.A.S.)
| | - Saskia Haitjema
- Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (S.W.v.d.L., M.A.S., S.H., H.M.d.R., G.P.)
| | - Hassan Foroughi Asl
- Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.F.A.)
| | - Ljubica Perisic
- Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (L.P., U.H.)
| | - Michal Mokry
- Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, University Utrecht, The Netherlands (M.M.).,Regenerative Medicine Center Utrecht, University Medical Center Utrecht, University Utrecht, The Netherlands (M.M.)
| | - Jessica van Setten
- Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (F.W.A., J.v.S.)
| | - Rainer Malik
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany (R.M., M.D.)
| | - Martin Dichgans
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany (R.M., M.D.).,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.)
| | - Bradford B Worrall
- Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville (B.B.W.)
| | | | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester (N.J.S.).,NIHR Leicester Biomedical Research Unit Centre, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom (N.J.S.)
| | - Heribert Schunkert
- Deutsches Herzzentrum München, Klinik an der TU München, Munich Heart Alliance (DZHK), Germany (H.S., J.E.)
| | - Jeanette Erdmann
- Deutsches Herzzentrum München, Klinik an der TU München, Munich Heart Alliance (DZHK), Germany (H.S., J.E.)
| | - Ulf Hedin
- Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (L.P., U.H.)
| | - Gabrielle Paulsson-Berne
- Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (G.P.-B.)
| | - Johan L M Björkegrenn
- CMM, Karolinska Institutet, Stockholm, Sweden. Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York (J.L.M.B.).,Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden (J.L.M.B.).,Clinical Gene Networks AB, Stockholm,Sweden (J.L.M.B.)
| | - Gert J de Borst
- Division of Surgical Specialties, Department of Surgery, University Medical Center Utrecht, University Utrecht, The Netherlands (G.J.d.B.)
| | - Folkert W Asselbergs
- Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (F.W.A., J.v.S.).,Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, University Utrecht, The Netherlands (P.I.W.d.B.).,Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, The Netherlands (P.I.W.d.B.).,Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, University Utrecht, The Netherlands (G.P.).,Durrer Center for Cardiogenetic Research, Netherlands Heart Institute, Utrecht (F.W.A.).,Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom (F.W.A.).,Institute of Health Informatics, University College London, London, United Kingdom (F.W.A.)
| | - Folkert W den Ruijter
- Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (F.W.A., J.v.S.)
| | - Paul I W de Bakker
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, University Utrecht, The Netherlands (P.I.W.d.B.).,Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, The Netherlands (P.I.W.d.B.)
| | - Gerard Pasterkamp
- Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (S.W.v.d.L., M.A.S., S.H., H.M.d.R., G.P.).,Department of Clinical Genetics, University Medical Center Utrecht, University Utrecht, The Netherlands (M.A.S.).,Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, University Utrecht, The Netherlands (G.P.)
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Tajbakhsh A, Bianconi V, Pirro M, Gheibi Hayat SM, Johnston TP, Sahebkar A. Efferocytosis and Atherosclerosis: Regulation of Phagocyte Function by MicroRNAs. Trends Endocrinol Metab 2019; 30:672-683. [PMID: 31383556 DOI: 10.1016/j.tem.2019.07.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/31/2022]
Abstract
There is evidence of the critical role of efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, in vascular cell homeostasis and protection against atherosclerosis. Specific microRNAs (miRs) can regulate atherogenesis by controlling the accumulation of professional phagocytes (e.g., macrophages) and nonprofessional phagocytes (i.e., neighboring tissue cells with the ability to acquire a macrophage-like phenotype) within the arterial wall, the differentiation of phagocytes into foam cells, the efferocytosis of apoptotic foam cells by phagocytes, and the phagocyte-mediated inflammatory response. A better understanding of the mechanisms involved in miR-regulated phagocyte function might lead to novel therapeutic antiatherosclerotic strategies. In this review, we try to shed light on the relationship between miRs and cellular players in the process of efferocytosis in the context of atherosclerotic plaque and their potential as molecular targets for novel antiatherosclerotic therapies.
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Affiliation(s)
- Amir Tajbakhsh
- Halal Research Center of IRI, FDA, Tehran, Iran; Department of Modern Sciences and Technologies, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vanessa Bianconi
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Seyed Mohammad Gheibi Hayat
- Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Science, Yazd, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Feng C, Chen Q, Fan M, Guo J, Liu Y, Ji T, Zhu J, Zhao X. Platelet-derived microparticles promote phagocytosis of oxidized low-density lipoprotein by macrophages, potentially enhancing foam cell formation. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:477. [PMID: 31700913 DOI: 10.21037/atm.2019.08.06] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background The interaction between platelets and macrophages plays an important role in the development and progression of atherosclerosis (AS). This study aimed to investigate the role of platelet microparticles (PMPs) in the development of foam cells. Methods PMPs are generated by activating platelets with thrombin and separated by ultracentrifugation. The macrophages were treated with PMPs, the phagocytosis of oxidized low-density lipoprotein (Ox-LDL) and formation of foam cells were evaluated by flow cytometry and confocal microscopy, respectively, and the inflammatory factors cytokines in the supernatant were detected by ELISA. Results PMPs significantly increase the phagocytosis of Ox-LDL and elevated foam cell formation of macrophages. IL-1β content in the supernatant of macrophages peaked around 2-4 h and declined to normal level after 6-8 h; IL-6 content peaked at 4 h and then decreased to normal level. TNF-α content peaked at 2-4 h. Conclusions The microparticles from activated platelets can increase the phagocytosis of Ox-LDL and the production of inflammatory cytokines by macrophages, which is related to the development of AS.
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Affiliation(s)
- Can Feng
- Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.,Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Qi Chen
- Department of Cardiology, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Min Fan
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Jun Guo
- Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yu Liu
- Department of Cardiology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing 210008, China
| | - Tao Ji
- Department of Neurosurgery, Tenth Affiliated Hospital, Tongji University, Shanghai 200072, China
| | - Jiaqi Zhu
- Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Xianxian Zhao
- Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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Inflammation‐regulatory microRNAs: Valuable targets for intracranial atherosclerosis. J Neurosci Res 2019; 97:1242-1252. [DOI: 10.1002/jnr.24487] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/24/2019] [Accepted: 06/10/2019] [Indexed: 12/16/2022]
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Circulating microRNA-378 levels serve as a novel biomarker for assessing the severity of coronary stenosis in patients with coronary artery disease. Biosci Rep 2019; 39:BSR20182016. [PMID: 31064817 PMCID: PMC6522732 DOI: 10.1042/bsr20182016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/05/2019] [Accepted: 05/02/2019] [Indexed: 01/22/2023] Open
Abstract
Background: Circulating microRNAs (miRNA) are steady preserved in blood plasma. Multiple evidences have shown that miRNAs play a crucial role in cardiovascular disease including miRNA-378, which has been illustrated to participate in diverse physiological and pathological processes of cardiovascular disease. In the present study, we aim to explore the expression of plasma miRNA-378 and its clinical significance in patients with coronary artery disease (CAD). Methods: MiRNA-378 expression in blood plasma was performed by quantitative real-time PCR (qRT-PCR) in 215 CAD patients and 52 matched controls of healthy populations. Medical information of all patients including the results of coronary angiography (CAG) was acquired through hospital information system (HIS). Spearman’s correlation, binary linear regression, and covariance analysis were used to examine the association between miRNA-378 and relative clinical risk factors. Receiver operating characteristic curve analysis was applied to evaluate the value of miRNA-378 in predicting the disease severity of coronary lesion. Results: Plasma miR-378 expression was significantly down-regulated in CAD patients compared with healthy controls. Relative miR-378 level was shown conversely correlated with Gensini score, which present the severity of coronary artery lesions. Moreover, it is indicated that miR-378 expression can effectively distinguish patients with or without coronary artery stenosis. Conclusions: Plasma miR-378 levels appear to be a promising non-invasive biomarker, but require to be further validated by a large cohort study in future.
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50
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Bollaert E, de Rocca Serra A, Demoulin JB. The HMG box transcription factor HBP1: a cell cycle inhibitor at the crossroads of cancer signaling pathways. Cell Mol Life Sci 2019; 76:1529-1539. [PMID: 30683982 PMCID: PMC11105191 DOI: 10.1007/s00018-019-03012-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/20/2018] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
HMG box protein 1 (HBP1) is a transcription factor and a potent cell cycle inhibitor in normal and cancer cells. HBP1 activates or represses the expression of different cell cycle genes (such as CDKN2A, CDKN1A, and CCND1) through direct DNA binding, cofactor recruitment, chromatin remodeling, or neutralization of other transcription factors. Among these are LEF1, TCF4, and MYC in the WNT/beta-catenin pathway. HBP1 also contributes to oncogenic RAS-induced senescence and terminal cell differentiation. Collectively, these activities suggest a tumor suppressor function. However, HBP1 is not listed among frequently mutated cancer driver genes. Nevertheless, HBP1 expression is lower in several tumor types relative to matched normal tissues. Several micro-RNAs, such as miR-155, miR-17-92, and miR-29a, dampen HBP1 expression in cancer cells of various origins. The phosphatidylinositol-3 kinase (PI3K)/AKT pathway also inhibits HBP1 transcription by preventing FOXO binding to the HBP1 promoter. In addition, AKT directly phosphorylates HBP1, thereby inhibiting its transcriptional activity. Taken together, these findings place HBP1 at the center of a network of micro-RNAs and oncoproteins that control cell proliferation. In this review, we discuss our current understanding of HBP1 function in human physiology and diseases.
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Affiliation(s)
- Emeline Bollaert
- Université Catholique de Louvain, de Duve Institute, Avenue Hippocrate 75, 1200, Brussels, Belgium
| | - Audrey de Rocca Serra
- Université Catholique de Louvain, de Duve Institute, Avenue Hippocrate 75, 1200, Brussels, Belgium
| | - Jean-Baptiste Demoulin
- Université Catholique de Louvain, de Duve Institute, Avenue Hippocrate 75, 1200, Brussels, Belgium.
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