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Severino P, D'Amato A, Prosperi S, Myftari V, Germanò R, Marek-Iannucci S, De Prisco A, Mariani MV, Marchiori L, Battaglia C, Tabacco L, Segato C, Mancone M, Fedele F, Vizza CD. Coronary microcirculation in myocardial ischemia: A genetic perspective. J Mol Cell Cardiol 2025; 203:67-75. [PMID: 40220989 DOI: 10.1016/j.yjmcc.2025.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Coronary microvascular dysfunction (CMD) is a major contributor to ischemic heart disease (IHD), acting both independently and together with atherosclerosis. CMD encompasses structural and functional microcirculatory changes that result in dysregulated coronary blood flow. Structural abnormalities include microvascular remodeling, resulting in arteriolar and capillary narrowing, perivascular fibrosis and capillary rarefaction. Endothelial dysfunction and smooth muscle cell hyperactivity further impair microcirculation. Genetic factors may play a crucial role in the pathophysiology of CMD, mainly due to single nucleotide polymorphisms (SNPs) in genes that regulate coronary blood flow and microcirculation structural modifications. This manuscript aims to review the genetic determinants of CMD, with particular focus on ion channels, microRNAs (miRNAs), and proteins involved in the endothelial environment. The improving knowledge about genetic aspects of CMD opens the possibility to have new biomarkers, improving diagnosis and the development of targeted treatments in light of an even more patient-tailored approach.
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Affiliation(s)
- Paolo Severino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Andrea D'Amato
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Silvia Prosperi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Vincenzo Myftari
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Rosanna Germanò
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Stefanie Marek-Iannucci
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Andrea De Prisco
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Marco Valerio Mariani
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Ludovica Marchiori
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Corinne Battaglia
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Leonardo Tabacco
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Camilla Segato
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Massimo Mancone
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | | | - Carmine Dario Vizza
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
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Li P, Wang F, Yue A, Xuan Y, Huang Y, Xu J, Weng J, Li Y, Sun K. LncRNA uc003pxg.1 Interacts With miR-339-5p Promote Vascular Endothelial Cell Proliferation, Migration and Angiogenesis. Korean Circ J 2025; 55:440-455. [PMID: 39733458 PMCID: PMC12088996 DOI: 10.4070/kcj.2024.0153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/29/2024] [Accepted: 10/09/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND AND OBJECTIVES This study aimed to investigate the roles of lncRNA uc003pxg.1 and miR-339-5p in regulating the occurrence and development of coronary heart disease. METHODS First, the expression levels of uc003pxg.1 and miR-339-5p were verified in peripheral blood mononuclear cells of clinical samples. Then, the target gene was identified using high-throughput sequencing combined with bioinformatics. Human umbilical vein endothelial cells (HUVECs) were transfected with si-uc003pxg.1, miR-339-5p mimic and miR-339-5p inhibitor, and the expression of related genes was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. EdU, CCK-8, Cell scratch and Transwell assays were used to analyze the effects of uc003pxg.1 and miR-339-5p on cell proliferation and migration. RESULTS The expression of uc003pxg.1 and miR-339-5p was negatively correlated in clinical samples and HUVECs. The si-uc003pxg.1 and miR-339-5p mimic decreased the proliferation and migration of HUVECs and decreased the expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). The protein expression levels of TGF-β1, α-SMA, CD31, collagen I, collagen III and endoglin were decreased, and angiogenesis was weakened. The miR-339-5p inhibitor had the opposite effect. CONCLUSIONS Our study revealed that upregulation of uc003pxg.1 and downregulation of miR-339-5p in vitro promote cell proliferation, cell migration and angiogenesis and upregulate the expression of TGF-β1, α-SMA, CD31, collagen I, collagen III and endoglin, which may lead to the development of vascular atherosclerosis.
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Affiliation(s)
- Ping Li
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
- Department of Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
| | - Feng Wang
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
- Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
| | - Anna Yue
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
| | - Yanling Xuan
- The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, P. R. China
| | - Ying Huang
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
- Department of Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
| | - Jingyi Xu
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
- Department of Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
| | - Jiayi Weng
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China
| | - Yuan Li
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China.
| | - Kangyun Sun
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, P. R. China.
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Hao Y, Li R, Fan C, Gao Y, Hou X, wen W, Shen Y. Identification and validation of mitophagy-related genes in acute myocardial infarction and ischemic cardiomyopathy and study of immune mechanisms across different risk groups. Front Immunol 2025; 16:1486961. [PMID: 40114920 PMCID: PMC11922711 DOI: 10.3389/fimmu.2025.1486961] [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: 08/27/2024] [Accepted: 02/17/2025] [Indexed: 03/22/2025] Open
Abstract
Introduction Acute myocardial infarction (AMI) is a critical condition that can lead to ischemic cardiomyopathy (ICM), a subsequent heart failure state characterized by compromised cardiac function. Methods This study investigates the role of mitophagy in the transition from AMI to ICM. We analyzed AMI and ICM datasets from GEO, identifying mitophagy-related differentially expressed genes (MRDEGs) through databases like GeneCards and Molecular Signatures Database, followed by functional enrichment and Protein-Protein Interaction analyses. Logistic regression, Support Vector Machine, and LASSO (Least Absolute Shrinkage and Selection Operator) were employed to pinpoint key MRDEGs and develop diagnostic models, with risk stratification performed using LASSO scores. Subgroup analyses included functional enrichment and immune infiltration analysis, along with protein domain predictions and the integration of regulatory networks involving Transcription Factors, miRNAs, and RNA-Binding Proteins, leading to drug target identification. Results The TGFβ pathway showed significant differences between high- and low-risk groups in AMI and ICM. Notably, in the AMI low-risk group, MRDEGs correlated positively with activated CD4+ T cells and negatively with Type 17 T helper cells, while in the AMI high-risk group, RPS11 showed a positive correlation with natural killer cells. In ICM, MRPS5 demonstrated a negative correlation with activated CD4+ T cells in the low-risk group and with memory B cells, mast cells, and dendritic cells in the high-risk group. The diagnostic accuracy of RPS11 was validated with an area under the curve (AUC) of 0.794 across diverse experimental approaches including blood samples, animal models, and myocardial hypoxia/reoxygenation models. Conclusions This study underscores the critical role of mitophagy in the transition from AMI to ICM, highlighting RPS11 as a highly significant biomarker with promising diagnostic potential and therapeutic implications.
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Affiliation(s)
- Ying Hao
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Medicine, Shanghai East Hospital Ji’an Hospital, Ji’an, Jiangxi, China
| | - RuiLin Li
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Medicine, Shanghai East Hospital Ji’an Hospital, Ji’an, Jiangxi, China
| | - ChengHui Fan
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Medicine, Shanghai East Hospital Ji’an Hospital, Ji’an, Jiangxi, China
| | - Yang Gao
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xia Hou
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wei wen
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - YunLi Shen
- Department of Cardiovascular Medicine, State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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Ding D, Zhao G. KLF9 aggravates the cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy through the lncRNA UCA1/p27 axis. Int J Exp Pathol 2025; 106:e12526. [PMID: 39909852 PMCID: PMC11798666 DOI: 10.1111/iep.12526] [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: 11/12/2024] [Accepted: 01/05/2025] [Indexed: 02/07/2025] Open
Abstract
Cardiac hypertrophy refers to an abnormal increase in the thickness of the heart muscle. Our study explores the role of Krüppel-like factor 9 (KLF9) in hypertrophic obstructive cardiomyopathy (HOCM)-induced cardiomyocyte hypertrophy, providing new targets for the treatment of HOCM. Cardiomyocytes were treated with isoproterenol (ISO). The levels of natriuretic peptide B (BNP)/natriuretic peptide A (ANP)/KLF9/long non-coding RNA urothelial carcinoma-associated 1 (lncRNA UCA1)/p27 were measured. Cell surface area and protein/DNA ratio were tested. The binding between KLF9 and the lncRNA UCA1 promoter and between zeste homologue 2 (EZH2) and lncRNA UCA1 was verified. The enrichment of histone H3 lysine 27 tri-methylation (H3K27me3) and EZH2 on the p27 promoter was analysed. ISO treatment increased KLF9 and lncRNA UCA1 expression and decreased p27 expression in cardiomyocytes. KLF9 knockdown inhibited ISO-induced cardiomyocyte hypertrophy, reduced ANP and BNP expression, and alleviated cardiomyocyte damage. KLF9 activated lncRNA UCA1 expression. LncRNA UCA1 recruited EZH2 to the p27 promoter region, increasing the enrichment of H3K27me3, thereby epigenetically suppressing p27 expression. LncRNA UCA1 overexpression or p27 downregulation reduced the protective effect of KLF9 downregulation on cardiomyocyte hypertrophy. In conclusion, KLF9 activates lncRNA UCA1 expression, and lncRNA UCA1 epigenetically suppresses p27 expression, thereby exacerbating cardiomyocyte hypertrophy in HOCM.
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Affiliation(s)
- Dayou Ding
- School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
| | - Guangrong Zhao
- School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
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Hayasaka T, Kawaguchi S, Sepúlveda MN, Teoh JP, Moukette B, Aonuma T, Madhur MS, Desai AA, Liangpunsakul S, Conway SJ, Kim IM. Cardiomyocyte-restricted MIAT deletion is sufficient to protect against murine myocardial infarction. Cell Death Discov 2025; 11:70. [PMID: 39979325 PMCID: PMC11842840 DOI: 10.1038/s41420-025-02352-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 01/28/2025] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
Myocardial infarction-associated transcript (MIAT), an intergenic long noncoding RNA (lncRNA), is conserved between rodents and humans and is directly linked to maladaptive cardiac remodeling in both patients and mouse models with various forms of heart failure (HF). We previously reported attenuation of cardiac stress, apoptosis, and fibrosis in a murine model of myocardial infarction (MI) with global MIAT ablation. Our transcriptomic profiling and mechanistic studies further revealed MIAT-induced activation of maladaptive genes, such as Hoxa4, Fmo2, Lrrn4, Marveld3, and Fat4. However, the source of MIAT and its contribution to MI and HF remain unknown. In this study, we generate a novel cardiomyocyte (CM)-specific MIAT conditional knockout mouse model, which exhibits improved cardiac function after MI. We further report that CM-specific MIAT ablation is sufficient to reduce cardiac damage, apoptosis, and fibrosis following chronic MI. Mechanistically, CM-specific MIAT deletion in mice leads to decreased expression of proapoptotic and pathological profibrotic genes, such as p53, Bak1, Col3a1, Col6a1, Postn, and Snail1 after chronic MI. These results enable us to begin to dissect cell-specific contributions to MIAT signaling and bolster the idea that MIAT plays a direct pathological role in CMs after MI.
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Affiliation(s)
- Taiki Hayasaka
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA
- Division of Cardiology and Nephrology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Satoshi Kawaguchi
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA
- Department of Emergency Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Marisa N Sepúlveda
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA
| | - Jian-Peng Teoh
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA
| | - Bruno Moukette
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA
- Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA
| | - Tatsuya Aonuma
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA
- Division of Cardiology and Nephrology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Meena S Madhur
- Division of Clinical Pharmacology, Indianapolis, IN, USA
| | - Ankit A Desai
- Krannert Cardiovascular Research Center, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Indianapolis, IN, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Simon J Conway
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Il-Man Kim
- Department of Anatomy, Cell Biology, and Physiology, Indianapolis, IN, USA.
- Krannert Cardiovascular Research Center, Indianapolis, IN, USA.
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
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Li S, Xu Z, Zhang S, Sun H, Qin X, Zhu L, Jiang T, Zhou J, Yan F, Deng Q. Non-coding RNAs in acute ischemic stroke: from brain to periphery. Neural Regen Res 2025; 20:116-129. [PMID: 38767481 PMCID: PMC11246127 DOI: 10.4103/nrr.nrr-d-23-01292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/09/2023] [Accepted: 12/18/2023] [Indexed: 05/22/2024] Open
Abstract
Acute ischemic stroke is a clinical emergency and a condition with high morbidity, mortality, and disability. Accurate predictive, diagnostic, and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined. With innovations in high-throughput gene sequencing analysis, many aberrantly expressed non-coding RNAs (ncRNAs) in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models. Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes, leading to neuroprotection or deterioration, thus ncRNAs can serve as therapeutic targets in acute ischemic stroke. Moreover, distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. In particular, ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke. In this review, we consolidate the latest progress of research into the roles of ncRNAs (microRNAs, long ncRNAs, and circular RNAs) in the pathological processes of acute ischemic stroke-induced brain damage, as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke.
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Affiliation(s)
- Shuo Li
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zhaohan Xu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Shiyao Zhang
- Department of Neurology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Huiling Sun
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiaodan Qin
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lin Zhu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Junshan Zhou
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Fuling Yan
- Department of Neurology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Qiwen Deng
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
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Caballero-Valderrama MDR, Bevilacqua E, Echevarría M, Salvador-Bofill FJ, Ordóñez A, López-Haldón JE, Smani T, Calderón-Sánchez EM. Early Myocardial Strain Reduction and miR-122-5p Elevation Associated with Interstitial Fibrosis in Anthracycline-Induced Cardiotoxicity. Biomedicines 2024; 13:45. [PMID: 39857629 PMCID: PMC11762338 DOI: 10.3390/biomedicines13010045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/12/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Echocardiographic myocardial strain is crucial for early detection of anthracycline-induced cardiotoxicity, particularly in patients at moderate or high risk. BACKGROUND/OBJECTIVES This study investigates changes in global longitudinal strain (GLS) in breast cancer patients with low baseline risk for cardiotoxicity during cancer therapy. We also examined the relationship between echocardiographic strain, structural myocardial changes, and microRNA (miRNA) dysregulation associated with cancer treatment using an animal model. METHODS Echocardiography and blood tests were examined in 33 breast cancer patients with low baseline risk for cardiotoxicity during anthracycline treatment, with a follow-up at 12 months. Additionally, 16 Wistar rats received epirubicin (20 mg/kg over 4 weeks) to examine cardiac strain and structural changes. Moreover, circulating miRNA levels were assessed in patients' serum using microarray at the end of the treatment and further analyzed in peripheral blood from the animal model. RESULTS Pathological GLS values were observed in 27.27% of patients after four cycles, with 15.15% showing reduced left ventricular ejection fraction (LVEF) after 12 months. In the animal model, epirubicin-induced circumferential strain (CS) decrease correlates with myocardial fibrosis assessed histologically and by a significant increase in COL1 and TGFB2 expression. Furthermore, we found a significant decrease in aquaporin1 expression associated with the presence of vacuoles in treated rats. Furthermore, dysregulation in the expression of miRNAs was observed in patients with cardiotoxicity. Among them, hsa-miR-122-5p is increased in both patient and rat serum post-treatment. CONCLUSIONS A notable percentage of low-risk patients exhibited cardiac strain reduction due to cardiotoxicity. Epirubicin treatment caused structural heart changes in rats, highlighting miR-122-5p as a potential fibrosis marker that correlated with echocardiographic parameters.
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Affiliation(s)
- María de Regla Caballero-Valderrama
- Cardiology Unit, University Hospital Virgen del Rocío, 41013 Seville, Spain; (M.d.R.C.-V.); (J.E.L.-H.)
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville-IBiS, University of Seville/Hospital Universitario Virgen de Rocio/CSIC, 41013 Seville, Spain; (E.B.); (A.O.); (T.S.)
| | - Elisa Bevilacqua
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville-IBiS, University of Seville/Hospital Universitario Virgen de Rocio/CSIC, 41013 Seville, Spain; (E.B.); (A.O.); (T.S.)
| | - Miriam Echevarría
- Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain;
| | | | - Antonio Ordóñez
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville-IBiS, University of Seville/Hospital Universitario Virgen de Rocio/CSIC, 41013 Seville, Spain; (E.B.); (A.O.); (T.S.)
| | - José Eduardo López-Haldón
- Cardiology Unit, University Hospital Virgen del Rocío, 41013 Seville, Spain; (M.d.R.C.-V.); (J.E.L.-H.)
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville-IBiS, University of Seville/Hospital Universitario Virgen de Rocio/CSIC, 41013 Seville, Spain; (E.B.); (A.O.); (T.S.)
| | - Tarik Smani
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville-IBiS, University of Seville/Hospital Universitario Virgen de Rocio/CSIC, 41013 Seville, Spain; (E.B.); (A.O.); (T.S.)
- Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain;
| | - Eva M. Calderón-Sánchez
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville-IBiS, University of Seville/Hospital Universitario Virgen de Rocio/CSIC, 41013 Seville, Spain; (E.B.); (A.O.); (T.S.)
- Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain;
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Liang R, Abudurexiti N, Wu J, Ling J, Peng Z, Yuan H, Wen S. Exosomes and miRNAs in Cardiovascular Diseases and Transcatheter Pulmonary Valve Replacement: Advancements, Gaps and Perspectives. Int J Mol Sci 2024; 25:13686. [PMID: 39769447 PMCID: PMC11727898 DOI: 10.3390/ijms252413686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/16/2025] Open
Abstract
As an important carrier of intercellular information transmission, exosomes regulate the physiological and pathological state of local or distant cells by carrying a variety of signal molecules such as microRNAs (miRNAs). Current research indicates that exosomes and miRNAs can serve as biomarkers and therapeutic targets for a variety of cardiovascular diseases (CVDs). This narrative review summarizes the research progress of exosomes and their miRNAs in CVDs, particularly in pulmonary valve diseases (PVDs), and, for the first time, explores their potential associations with transcatheter pulmonary valve replacement (TPVR). Currently, miRNAs play a crucial role in determining the optimal timing for TPVR intervention, and they demonstrate broad application prospects in post-TPVR right ventricular (RV) remodeling, treatment, and prognosis monitoring. However, the association between exosomes and miRNAs and the development of PVDs, particularly pulmonary regurgitation, remains unclear. The molecular mechanisms of exosomes and miRNAs in PVDs and RV remodeling after TPVR have not been fully elucidated, and their application in postoperative treatment following TPVR is still in its infancy. Future research must focus on advancing fundamental studies, validating biomarkers, and enhancing clinical applications to achieve significant breakthroughs.
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Affiliation(s)
- Runzhang Liang
- Department of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (R.L.); (J.W.)
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
| | - Naijimuding Abudurexiti
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
| | - Jiaxiong Wu
- Department of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (R.L.); (J.W.)
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
| | - Jing Ling
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
| | - Zirui Peng
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
| | - Haiyun Yuan
- Department of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (R.L.); (J.W.)
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
| | - Shusheng Wen
- Department of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (R.L.); (J.W.)
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (N.A.); (J.L.); (Z.P.)
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9
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Tan J, Min J, Jiang Y, Liu S, Ke M, Wang Z, Yang HT. CircCHSY1 protects hearts against ischaemia/reperfusion injury by enhancing heme oxygenase 1 expression via miR-24-3p. Cardiovasc Res 2024; 120:1924-1938. [PMID: 39082269 DOI: 10.1093/cvr/cvae162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 03/14/2024] [Accepted: 05/03/2024] [Indexed: 12/11/2024] Open
Abstract
AIMS Circular RNAs (circRNAs) are important players involved in a variety of physiological and pathological processes. However, their functions and mechanisms during myocardial ischaemic injury and protection remain largely unknown. We recently found significant alterations of many circRNAs including circCHSY1 following myocardial ischaemia/reperfusion (I/R) injury, whereas their exact functions are unclear. Here, we investigated the roles of circCHSY1 in the acute myocardial I/R injury and the potential mechanisms involved. METHODS AND RESULTS The expression of circCHSY1 was detected in cardiomyocytes from mouse, rat, and human embryonic stem cells (hESC-CMs). It was further up-regulated in mouse I/R (30 min/24 h) hearts, oxygen glucose deprivation/reperfusion (OGD/R, 6 h/2 h) primary neonatal rat ventricular cardiomyocytes (NRCMs) and OGD/R (48 h/2 h) hESC-CMs. Adenovirus-mediated circCHSY1 overexpression significantly decreased infarct size and lactate dehydrogenase (LDH) release in mouse I/R hearts. Consistently, circCHSY1 overexpression reduced the LDH release in the OGD/R NRCMs and hESC-CMs, improved cell viability, and preserved mitochondrial function in the OGD/R NRCMs, whereas there were no significant differences in cell viability and LDH release between the OGD/R NRCMs with and without small interfering RNA (siRNA)-mediated circCHSY1 knockdown. Mechanistically, circCHSY1 was detected to bind with miR-24-3p analysed by dual-luciferase assay and RNA pull-down assays. CircCHSY1 overexpression-mediated protective effects on cells and mitochondria in OGD/R NRCMs were reversed by the miR-24-3p mimic. Furthermore, dual-luciferase assay showed that miR-24-3p was directly bound to heme oxygenase 1 (HO1) via its 3'UTR. The protein level of HO1 was down-regulated by miR-24-3p mimic in OGD/R NRCMs but enhanced by the circCHSY1 overexpression in vitro and in vivo. Functionally, the HO1 knockdown by adenovirus in vivo and by siRNA in vitro eliminated cardioprotective effects of circCHSY1 overexpression. CONCLUSION CircCHSY1 is up-regulated following myocardial I/R injury. The higher level of circCHSY1 protects I/R hearts and cardiomyocytes. The protection of circCHSY1 is mediated through enhancement of the HO1 level, resulting in preserving mitochondrial homoeostasis via targeting miR-24-3p in cardiomyocytes. These findings suggest circCHSY1 as a protective factor.
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MESH Headings
- Animals
- MicroRNAs/metabolism
- MicroRNAs/genetics
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Myocardial Reperfusion Injury/enzymology
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/genetics
- Myocardial Reperfusion Injury/metabolism
- Myocardial Reperfusion Injury/prevention & control
- Humans
- RNA, Circular/metabolism
- RNA, Circular/genetics
- Disease Models, Animal
- Mice, Inbred C57BL
- Male
- Cells, Cultured
- Human Embryonic Stem Cells/metabolism
- Human Embryonic Stem Cells/enzymology
- Human Embryonic Stem Cells/pathology
- Myocardial Infarction/enzymology
- Myocardial Infarction/pathology
- Myocardial Infarction/metabolism
- Myocardial Infarction/genetics
- Myocardial Infarction/prevention & control
- Signal Transduction
- Rats, Sprague-Dawley
- Heme Oxygenase-1/metabolism
- Heme Oxygenase-1/genetics
- Mitochondria, Heart/enzymology
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Rats
- 3' Untranslated Regions
- Heme Oxygenase (Decyclizing)
- Membrane Proteins
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Affiliation(s)
- Jiliang Tan
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, 320 Yue Yang Road, Shanghai 200031, P.R. China
| | - Jie Min
- Department of Cardiovascular Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai 200003, P.R. China
| | - Yun Jiang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, 320 Yue Yang Road, Shanghai 200031, P.R. China
| | - Shenyan Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, 320 Yue Yang Road, Shanghai 200031, P.R. China
| | - Minxia Ke
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, 320 Yue Yang Road, Shanghai 200031, P.R. China
| | - Zhinong Wang
- Department of Cardiovascular Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai 200003, P.R. China
| | - Huang-Tian Yang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, 320 Yue Yang Road, Shanghai 200031, P.R. China
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10
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Alissa M, Aldurayhim M, Abdulaziz O, Alsalmi O, Awad A, Algopishi UB, Alharbi S, Safhi AY, Khan KH, Uffar C. From molecules to heart regeneration: Understanding the complex and profound role of non-coding RNAs in stimulating cardiomyocyte proliferation for cardiac repair. Curr Probl Cardiol 2024; 49:102857. [PMID: 39306148 DOI: 10.1016/j.cpcardiol.2024.102857] [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: 09/07/2024] [Accepted: 09/16/2024] [Indexed: 09/29/2024]
Abstract
Recent studies of noncoding genomes have shown important implications for regulating gene expression and genetic programs during development and their association with health, including cardiovascular disease. There are nearly 2,500 microRNAs (miRNAs), 12,000 long-chain non-coding RNAs (lncRNA), and nearly 4,000 circular RNAs (circles). Even though they do not code for proteins, they make up nearly 99% of the human genome. Non-coding RNA families (ncRNAs) have recently been discovered and established as novel and necessary controllers of cardiovascular risk factors and cellular processes and, therefore, have the potential to improve the diagnosis and prediction of cardiovascular disease. The increase in the prevalence of cardiovascular disease can be explained by the shortcomings of existing therapies, which focus only on the non-coding RNAs that protein codes for. On the other hand, recent studies point to the possibility of using ncRNAs in the early detection and intervention of CVD. These findings suggest that developing diagnostic tools and therapies based on miRNAs, lncRNAs, and circRNAs will potentially enhance the clinical management of patients with cardiovascular disease. Cardiovascular diseases include CH, HF, RHD, ACS, MI, AS, MF, ARR, and PAH, of which CH is the most common cardiovascular disease, followed by HF and RHD. This paper aims to elucidate the biological and clinical significance of miRNAs, increase, and circles, as well as their expression profiles and the possibility of regulating non-coding transcripts in cardiovascular diseases to improve the application of ncRNAs in diagnosis and treatment.
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Affiliation(s)
- Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Mohammed Aldurayhim
- Department of Medical Laboratory, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Osama Abdulaziz
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21974, Saudi Arabia
| | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21974, Saudi Arabia
| | - Alsamghan Awad
- King Khalid University, College of Medicine, Family Medicine department, Saudi Arabia
| | | | - Sarah Alharbi
- Department of Medical Laboratory, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Awaji Y Safhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Khadijah Hassan Khan
- Department of Laboratory, King Faisal Medical Complex, Ministry of Health, Taif 26514, Saudi Arabia
| | - Christin Uffar
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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11
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Loreni F, Nenna A, Nappi F, Ferrisi C, Chello C, Lusini M, Vincenzi B, Tonini G, Chello M. miRNAs in the diagnosis and therapy of cardiac and mediastinal tumors: a new dawn for cardio-oncology? Future Cardiol 2024; 20:795-806. [PMID: 39513219 PMCID: PMC11622773 DOI: 10.1080/14796678.2024.2419225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 10/17/2024] [Indexed: 11/15/2024] Open
Abstract
Dysfunctions in miRNA production have been recently investigated as predictors of neoplasms and their therapeutic strategies. In this review, we summarize the available knowledge on miRNAs and cardiac tumors (such as myxoma) and mediastinal tumors (such as thymoma) and propose new avenues for future research. MiRNAs are crucial for cardiac development through the expression of cardiac transcription factors (miR-335-5p), hinder the cell cycle by modulating the activity of transcription factors (miR-126-3p, miR-320a), modulate the production of inflammatory factors such as interleukins (miR-217), and interfere with cell proliferation or apoptosis (miR-218, miR-634 and miR-122). Current and future research on miRNAs is essential, as a deep understanding could lead to a revolution in the field of diagnostics and prevention of neoplastic diseases.
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Affiliation(s)
- Francesco Loreni
- Cardiac Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
| | - Antonio Nenna
- Cardiac Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
| | - Francesco Nappi
- Cardiac Surgery, Centre Cardiologique du Nord, Saint Denis, 93200, France
| | - Chiara Ferrisi
- Cardiac Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
| | - Camilla Chello
- PhD Course of Integrated Biomedical Sciences, Università Campus Bio-Medico di Roma, Rome, 00128, Italy
| | - Mario Lusini
- Cardiac Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
| | - Bruno Vincenzi
- Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
| | - Giuseppe Tonini
- Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
| | - Massimo Chello
- Cardiac Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, 00128, Italy
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12
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Wang Y, Lai J, Chen Z, Sun L, Ma Y, Wu J. Exploring the therapeutic mechanisms of heart failure with Chinese herbal medicine: a focus on miRNA-mediated regulation. Front Pharmacol 2024; 15:1475975. [PMID: 39564110 PMCID: PMC11573571 DOI: 10.3389/fphar.2024.1475975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 10/23/2024] [Indexed: 11/21/2024] Open
Abstract
Heart failure (HF) is a clinical condition caused by abnormalities in the heart's structure or function, primarily manifested as diminished ability of the heart to pump blood, which leads to compensatory activation of neurohormones and increased left ventricular filling pressure. HF is one of the fastest-growing cardiovascular diseases globally in terms of incidence and mortality, negatively impacting patients' quality of life and imposing significant medical and economic burdens. Despite advancements in the treatment of HF, hospitalization and mortality remain rates high. In China, Chinese herbal medicine (CHM) has historically played a prominent role in addressing HF, with significant proven efficacy. MicroRNA (miRNA) exerts a pivotal regulatory influence on the maintenance of regular cardiac activity and the progression of HF. MiRNAs, a category of single-stranded RNA molecules, are characterized by their inability to code for proteins. They regulate gene expression by binding to the 3'-untranslated region (3'-UTR) of target mRNAs, thereby influencing the onset and progression of various diseases. Abnormal expression of specific miRNAs is closely associated with HF pathological processes, such as cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy. This abnormal expression can influence the pathological progression of HF through the regulation of miRNA expression. This article reviews the regulatory role of miRNAs in HF pathology discusses how CHM compounds and their active ingredients can ameliorate HF pathology through the regulation of miRNA expression. In conclusion, miRNAs represent promising therapeutic targets for HF, and CHM provides a novel strategy for treatment through the regulation of miRNA expression. Future studies must delve deeper into the precise mechanisms by which CHM modulates miRNAs and fully explore its potential for clinical application in HF treatment.
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Affiliation(s)
- Yang Wang
- Department of Postgraduate, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Junyu Lai
- Department of Cardiovascular, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Zhengtao Chen
- Department of Cardiovascular, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Liqiang Sun
- Department of Cardiovascular, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Yirong Ma
- Department of Postgraduate, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Jianguang Wu
- Department of Cardiovascular, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
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13
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Zhang J. Non-coding RNAs and angiogenesis in cardiovascular diseases: a comprehensive review. Mol Cell Biochem 2024; 479:2921-2953. [PMID: 38306012 DOI: 10.1007/s11010-023-04919-5] [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: 10/27/2023] [Accepted: 12/18/2023] [Indexed: 02/03/2024]
Abstract
Non-coding RNAs (ncRNAs) have key roles in the etiology of many illnesses, including heart failure, myocardial infarction, stroke, and in physiological processes like angiogenesis. In transcriptional regulatory circuits that control heart growth, signaling, and stress response, as well as remodeling in cardiac disease, ncRNAs have become important players. Studies on ncRNAs and cardiovascular disease have made great progress recently. Here, we go through the functions of non-coding RNAs (ncRNAs) like circular RNAs (circRNAs), and microRNAs (miRNAs) as well as long non-coding RNAs (lncRNAs) in modulating cardiovascular disorders.
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Affiliation(s)
- Jie Zhang
- Medical School, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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14
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Jing MR, Liang XY, Zhang YX, Zhu YW, Wang Y, Chu T, Jin YQ, Zhang CH, Zhu SG, Zhang CJ, Wang QM, Feng ZF, Ji XY, Wu DD. Role of hydrogen sulfide-microRNA crosstalk in health and disease. Nitric Oxide 2024; 152:19-30. [PMID: 39260562 DOI: 10.1016/j.niox.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/15/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
The mutual regulation between hydrogen sulfide (H2S) and microRNA (miRNA) is involved in the development of many diseases, including cancer, cardiovascular disease, inflammatory disease, and high-risk pregnancy. Abnormal expressions of endogenous H2S-producing enzyme and miRNA in tissues and cells often indicate the occurrence of diseases, so the maintenance of their normal levels in the body can mitigate damages caused by various factors. Many studies have found that H2S can promote the migration, invasion, and proliferation of cancer cells by regulating the expression of miRNA, while many H2S donors can inhibit cancer progression by interfering with the proliferation, apoptosis, cell cycle, metastasis, and angiogenesis of cancer cells. Furthermore, the mutual regulation between H2S and miRNA can also prevent cell injury in cardiovascular disease and inflammatory disease through anti-inflammation, anti-oxidation, anti-apoptosis, and pro-autophagy. In addition, H2S can promote angiogenesis and relieve vasoconstriction by regulating the expression of miRNA, thereby improving fetal growth in high-risk pregnancy. In this review, we discuss the mechanism of mutual regulation between H2S and miRNA in various diseases, which may provide reliable therapeutic targets for these diseases.
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Affiliation(s)
- Mi-Rong Jing
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xiao-Yi Liang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yan-Xia Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yi-Wen Zhu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yan Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Ti Chu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yu-Qing Jin
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Chuan-Hao Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Shuai-Gang Zhu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Chao-Jing Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Qi-Meng Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Zhi-Fen Feng
- School of Nursing and Health, Henan University, Kaifeng, Henan, 475004, China.
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China; Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Zhengzhou, Henan, 450064, China.
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China; Kaifeng Key Laboratory of Cell Signal Transduction, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China; Department of Stomatology, Huaihe Hospital of Henan University, School of Stomatology, Henan University, Kaifeng, Henan, 475004, China.
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15
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Du H, Zhao Y, Wen J, Dai B, Hu G, Zhou Y, Yin Z, Ding N, Li H, Fan J, Nie X, Wang F, Liu Q, Wen Z, Xu G, Wang DW, Chen C. LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1. Circulation 2024; 150:1030-1049. [PMID: 38841852 DOI: 10.1161/circulationaha.123.067861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 05/15/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Dilated cardiomyopathy is characterized by left ventricular dilation and continuous systolic dysfunction. Mitochondrial impairment is critical in dilated cardiomyopathy; however, the underlying mechanisms remain unclear. Here, we explored the cardioprotective role of a heart-enriched long noncoding RNA, the dilated cardiomyopathy repressive transcript (DCRT), in maintaining mitochondrial function. METHODS The DCRT knockout (DCRT-/-) mice and DCRT knockout cells were developed using CRISPR-Cas9 technology. Cardiac-specific DCRT transgenic mice were generated using α-myosin heavy chain promoter. Chromatin coimmunoprecipitation, RNA immunoprecipitation, Western blot, and isoform sequencing were performed to investigate the underlying mechanisms. RESULTS We found that the long noncoding RNA DCRT was highly enriched in the normal heart tissues and that its expression was significantly downregulated in the myocardium of patients with dilated cardiomyopathy. DCRT-/- mice spontaneously developed cardiac dysfunction and enlargement with mitochondrial impairment. DCRT transgene or overexpression with the recombinant adeno-associated virus system in mice attenuated cardiac dysfunction induced by transverse aortic constriction treatment. Mechanistically, DCRT inhibited the third exon skipping of NDUFS2 (NADH dehydrogenase ubiquinone iron-sulfur protein 2) by directly binding to PTBP1 (polypyrimidine tract binding protein 1) in the nucleus of cardiomyocytes. Skipping of the third exon of NDUFS2 induced mitochondrial dysfunction by competitively inhibiting mitochondrial complex I activity and binding to PRDX5 (peroxiredoxin 5) and suppressing its antioxidant activity. Furthermore, coenzyme Q10 partially alleviated mitochondrial dysfunction in cardiomyocytes caused by DCRT reduction. CONCLUSIONS Our study revealed that the loss of DCRT contributed to PTBP1-mediated exon skipping of NDUFS2, thereby inducing cardiac mitochondrial dysfunction during dilated cardiomyopathy development, which could be partially treated with coenzyme Q10 supplementation.
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MESH Headings
- Animals
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Cardiomyopathy, Dilated/pathology
- Polypyrimidine Tract-Binding Protein/genetics
- Polypyrimidine Tract-Binding Protein/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Mice
- Alternative Splicing
- Humans
- Mice, Knockout
- Heterogeneous-Nuclear Ribonucleoproteins/genetics
- Heterogeneous-Nuclear Ribonucleoproteins/metabolism
- Electron Transport Complex I/metabolism
- Electron Transport Complex I/genetics
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Male
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Mitochondria, Heart/genetics
- Mice, Transgenic
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Affiliation(s)
- Hengzhi Du
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Yanru Zhao
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Jianpei Wen
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Beibei Dai
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Guo Hu
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Yufei Zhou
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Zhongwei Yin
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Nan Ding
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Huaping Li
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Jiahui Fan
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Xiang Nie
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Feng Wang
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Qian Liu
- Tongji Hospital, and Department of Forensic Medicine (Q.L.), Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Wen
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Gang Xu
- Divisions of Cardiology and Nephrology (G.X.), Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
| | - Chen Chen
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (H.D., Y.Z., J.W., B.D., G.H., Y.Z., Z.Y., N.D., H.L., J.F., X.N., F.W., Z.W., D.W.W., C.C.)
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16
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Cabiati M, Federico G, Del Ry S. Importance of Studying Non-Coding RNA in Children and Adolescents with Type 1 Diabetes. Biomedicines 2024; 12:1988. [PMID: 39335501 PMCID: PMC11429055 DOI: 10.3390/biomedicines12091988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/21/2024] [Accepted: 08/26/2024] [Indexed: 09/30/2024] Open
Abstract
Type 1 diabetes (T1D) mellitus is a chronic illness in children and teens, with rising global incidence rates. It stems from an autoimmune attack on pancreatic β cells, leading to insufficient insulin production. Genetic susceptibility and environmental triggers initiate this process. Early detection is possible by identifying multiple autoantibodies, which aids in predicting future T1D development. A new staging system highlights T1D's onset with islet autoimmunity rather than symptoms. Family members of T1D patients face a significantly increased risk of T1D. Italy recently passed a law mandating national T1D screening for pediatric populations. Measurements of β cell function continue to be essential in assessing efficacy, and different models have been proposed, but more appropriate biomarkers are mandatory for both progression studies before the onset of diabetes and during therapeutic monitoring. Biomarkers like microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) play key roles in T1D pathogenesis by regulating gene expression. Understanding their roles offers insights into T1D mechanisms and potential therapeutic targets. In this review, we summarized recent progress in the roles of some non-coding RNAs (ncRNAs) in the pathogenesis of T1D, with particular attention to miRNAs, lncRNAs, and circRNAs.
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Affiliation(s)
- Manuela Cabiati
- Laboratory of Biochemistry and Molecular Biology, Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy
| | - Giovanni Federico
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Silvia Del Ry
- Laboratory of Biochemistry and Molecular Biology, Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy
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17
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Ejikeme C, Safdar Z. Exploring the pathogenesis of pulmonary vascular disease. Front Med (Lausanne) 2024; 11:1402639. [PMID: 39050536 PMCID: PMC11267418 DOI: 10.3389/fmed.2024.1402639] [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: 03/18/2024] [Accepted: 06/26/2024] [Indexed: 07/27/2024] Open
Abstract
Pulmonary hypertension (PH) is a complex cardiopulmonary disorder impacting the lung vasculature, resulting in increased pulmonary vascular resistance that leads to right ventricular dysfunction. Pulmonary hypertension comprises of 5 groups (PH group 1 to 5) where group 1 pulmonary arterial hypertension (PAH), results from alterations that directly affect the pulmonary arteries. Although PAH has a complex pathophysiology that is not completely understood, it is known to be a multifactorial disease that results from a combination of genetic, epigenetic and environmental factors, leading to a varied range of symptoms in PAH patients. PAH does not have a cure, its incidence and prevalence continue to increase every year, resulting in higher morbidity and mortality rates. In this review, we discuss the different pathologic mechanisms with a focus on epigenetic modifications and their roles in the development and progression of PAH. These modifications include DNA methylation, histone modifications, and microRNA dysregulation. Understanding these epigenetic modifications will improve our understanding of PAH and unveil novel therapeutic targets, thus steering research toward innovative treatment strategies.
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Affiliation(s)
| | - Zeenat Safdar
- Department of Pulmonary-Critical Care Medicine, Houston Methodist Lung Center, Houston Methodist Hospital, Houston, TX, United States
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18
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Zhang J, Tian Z, Qin C, Momeni MR. The effects of exercise on epigenetic modifications: focus on DNA methylation, histone modifications and non-coding RNAs. Hum Cell 2024; 37:887-903. [PMID: 38587596 DOI: 10.1007/s13577-024-01057-y] [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: 01/04/2024] [Accepted: 03/10/2024] [Indexed: 04/09/2024]
Abstract
Physical activity on a regular basis has been shown to bolster the overall wellness of an individual; research is now revealing that these changes are accompanied by epigenetic modifications. Regular exercise has been proven to make intervention plans more successful and prolong adherence to them. When it comes to epigenetic changes, there are four primary components. This includes changes to the DNA, histones, expression of particular non-coding RNAs and DNA methylation. External triggers, such as physical activity, can lead to modifications in the epigenetic components, resulting in changes in the transcription process. This report pays attention to the current knowledge that pertains to the epigenetic alterations that occur after exercise, the genes affected and the resulting characteristics.
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Affiliation(s)
- Junxiong Zhang
- Xiamen Academy of Art and Design, Fuzhou University, Xiamen, 361024, Fujian, China.
| | - Zhongxin Tian
- College of Physical Education, Taiyuan University of Technology, Taiyuan, 030024, Shanxi, China.
| | - Chao Qin
- College of Physical Education, Taiyuan University of Technology, Taiyuan, 030024, Shanxi, China
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19
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Völkers M, Preiss T, Hentze MW. RNA-binding proteins in cardiovascular biology and disease: the beat goes on. Nat Rev Cardiol 2024; 21:361-378. [PMID: 38163813 DOI: 10.1038/s41569-023-00958-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
Cardiac development and function are becoming increasingly well understood from different angles, including signalling, transcriptional and epigenetic mechanisms. By contrast, the importance of the post-transcriptional landscape of cardiac biology largely remains to be uncovered, building on the foundation of a few existing paradigms. The discovery during the past decade of hundreds of additional RNA-binding proteins in mammalian cells and organs, including the heart, is expected to accelerate progress and has raised intriguing possibilities for better understanding the intricacies of cardiac development, metabolism and adaptive alterations. In this Review, we discuss the progress and new concepts on RNA-binding proteins and RNA biology and appraise them in the context of common cardiovascular clinical conditions, from cell and organ-wide perspectives. We also discuss how a better understanding of cardiac RNA-binding proteins can fill crucial knowledge gaps in cardiology and might pave the way to developing better treatments to reduce cardiovascular morbidity and mortality.
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Affiliation(s)
- Mirko Völkers
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg and Mannheim, Germany
| | - Thomas Preiss
- Shine-Dalgarno Centre for RNA Innovation, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - Matthias W Hentze
- European Molecular Biology Laboratory, Heidelberg, Germany.
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.
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20
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Olson SR, Tang WHW, Liu CF. Non-Coding Ribonucleic Acids as Diagnostic and Therapeutic Targets in Cardiac Fibrosis. Curr Heart Fail Rep 2024; 21:262-275. [PMID: 38485860 PMCID: PMC11090942 DOI: 10.1007/s11897-024-00653-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/26/2024] [Indexed: 05/14/2024]
Abstract
PURPOSE OF REVIEW Cardiac fibrosis is a crucial juncture following cardiac injury and a precursor for many clinical heart disease manifestations. Epigenetic modulators, particularly non-coding RNAs (ncRNAs), are gaining prominence as diagnostic and therapeutic tools. RECENT FINDINGS miRNAs are short linear RNA molecules involved in post-transcriptional regulation; lncRNAs and circRNAs are RNA sequences greater than 200 nucleotides that also play roles in regulating gene expression through a variety of mechanisms including miRNA sponging, direct interaction with mRNA, providing protein scaffolding, and encoding their own products. NcRNAs have the capacity to regulate one another and form sophisticated regulatory networks. The individual roles and disease relevance of miRNAs, lncRNAs, and circRNAs to cardiac fibrosis have been increasingly well described, though the complexity of their interrelationships, regulatory dynamics, and context-specific roles needs further elucidation. This review provides an overview of select ncRNAs relevant in cardiac fibrosis as a surrogate for many cardiac disease states with a focus on crosstalk and regulatory networks, variable actions among different disease states, and the clinical implications thereof. Further, the clinical feasibility of diagnostic and therapeutic applications as well as the strategies underway to advance ncRNA theranostics is explored.
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Affiliation(s)
- Samuel R Olson
- Medicine Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - W H Wilson Tang
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
- Kaufman Center for Heart Failure Treatment and Recovery, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Chia-Feng Liu
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
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21
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Xiong T, Jia Y, Tan F, Long X, Yuan X, She Q, Du J. Integrated analysis reveals ceRNA network of cardiac remodeling by SGLT2 inhibitor in middle-aged hypertensive rats. Biochem Biophys Res Commun 2024; 696:149434. [PMID: 38198921 DOI: 10.1016/j.bbrc.2023.149434] [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: 10/23/2023] [Revised: 12/18/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent an innovative class of antidiabetic agents that have demonstrated promise in mitigating cardiac remodeling. However, the transcriptional regulatory mechanisms underpinning their impact on blood pressure and the reversal of hypertension-induced cardiac remodeling remain largely unexplored. Given this context, our study concentrated on comparing the cardiac expression profiles of lncRNAs and mRNAs between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). To validate our results, we performed blood pressure measurements, tissue staining, and qRT-PCR. The treatment led to a significant reduction in systolic blood pressure and improved cardiac remodeling by reducing myocardial fibrosis and regulating the inflammatory response. Our examination disclosed that ventricular tissue mRNA, regulated by hypertension, was primarily concentrated in the complement and coagulation cascades and cytokine-cytokine receptor interactions. Compared with SHR, the SGLT2i treatment group was associated with myocardial contraction. Investigation into the lncRNA-mRNA regulatory network and competing endogenous RNA (ceRNA) network suggested that the potential roles of these differentially expressed (DE) lncRNAs and mRNAs were tied to processes such as collagen fibril organization, inflammatory response, and extracellular matrix (ECM) modifications. We found that the expression of Col3a1, C1qa, and lncRNA NONRATT007139.2 were altered in the SHR group and that SGLT2i treatment reversed these changes. Our results suggest that dapagliflozin effectively reverses hypertension-induced myocardial remodeling through a lncRNA-mRNA transcriptional regulatory network, with immune cell-mediated ECM deposition as a potential regulatory target. This underlines the potentiality of SGLT2i and genes related to immunity as promising targets for the treatment of hypertension.
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Affiliation(s)
- Tianhua Xiong
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuewang Jia
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fangyan Tan
- Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xianglin Long
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Yuan
- Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang She
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianlin Du
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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22
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Forte M, Sarto G, Sciarretta S. miR-93 and synaptotagmin-7: two novel players in the regulation of autophagy during cardiac hypertrophy. FEBS J 2024; 291:441-444. [PMID: 38037874 DOI: 10.1111/febs.17008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 11/17/2023] [Indexed: 12/02/2023]
Abstract
The molecular mechanisms involved in the transition of cardiac hypertrophy to heart failure (HF) are not fully characterized. Autophagy is a catabolic, self-renewal intracellular mechanism, which protects the heart during HF. In the heart of a mouse model of angiotensin-II-induced hypertrophy, Sun and colleagues demonstrated that reduced levels of miR-93 lead to synaptotagmin-7 (Syt-7) upregulation and consequent inhibition of autophagy. miR-93 overexpression or syt-7 inhibition rescues autophagy and maladaptive hypertrophy. This research identifies new players in the pathophysiology of cardiac hypertrophy, opening innovative therapeutic perspectives. miR-93 may also be considered in the future as a novel circulating biomarker for patients at high risk to develop HF.
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Affiliation(s)
| | | | - Sebastiano Sciarretta
- IRCCS Neuromed, Pozzilli, Italy
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
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23
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Haybar H, Sadati NS, Purrahman D, Mahmoudian-Sani MR, Saki N. lncRNA TUG1 as potential novel biomarker for prognosis of cardiovascular diseases. Epigenomics 2023; 15:1273-1290. [PMID: 38088089 DOI: 10.2217/epi-2023-0242] [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] [Indexed: 01/05/2024] Open
Abstract
Globally, cardiovascular diseases (CVDs) are among the leading causes of death. In light of the high prevalence and mortality of CVDs, it is imperative to understand the molecules involved in CVD pathogenesis and the signaling pathways that they initiate. This may facilitate the development of more precise and expedient diagnostic techniques, the identification of more effective prognostic molecules and the identification of potential therapeutic targets. Numerous studies have examined the role of lncRNAs, such as TUG1, in CVD pathogenesis in recent years. According to this review article, TUG1 can be considered a biomarker for predicting the prognosis of CVD.
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Affiliation(s)
- Habib Haybar
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Narjes Sadat Sadati
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Daryush Purrahman
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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24
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Huang Y, Li Y, Zhang K, Xu J, Li P, Yan X, Sun K. Expression and diagnostic value of PIWI-interacting RNA by serum in acute myocardial infarction. J Cardiol 2023; 82:441-447. [PMID: 37422074 DOI: 10.1016/j.jjcc.2023.06.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 06/13/2023] [Accepted: 06/30/2023] [Indexed: 07/10/2023]
Abstract
OBJECTIVE To detect the expression level of PIWI-interacting RNA in the serum of patients with acute myocardial infarction, and to explore the role of PIWI-interacting RNA in acute myocardial infarction. METHODS RNA was extracted from the serum of acute myocardial infarction patients and healthy subjects, and high-throughput sequencing of PIWI-interacting RNAs was performed to screen differentially expressed PIWI-interacting RNAs. Quantitative polymerase chain reaction was used to detect the expression of four differentially expressed PIWI-interacting RNAs in 52 patients with acute myocardial infarction and 30 healthy people. Receiver operating characteristic (ROC) curve was further used to analyze the correlation between differentially expressed PIWI-interacting RNAs and the occurrence of acute myocardial infarction. Kyoto Encyclopedia of Genes and Genomes analysis was used to analyze the role of PIWI-interacting RNA in the occurrence of acute myocardial infarction. RESULTS RNA sequencing and bioinformatics analysis revealed that most piRNAs were upregulated in AMI patients, with 195 upregulated and 13 downregulated. Among them, piR-hsa-9010, piR-hsa-28646, and piR-hsa-23619 were significantly up-regulated in the serum of patients with acute myocardial infarction, but their expression in the acute heart failure group and coronary heart disease group was not significantly different from that in the healthy group. ROC curve analysis showed that piR-hsa-9010, piR-hsa-28646, and piR-hsa-23619 had high diagnostic values in acute myocardial infarction. In vitro, there was no significant difference in the expression of piR-hsa-9010 among THP-1, HUVEC, and AC16, while the expression of piR-hsa-28646 and piR-hsa-23619 in HUVEC was significantly higher than that in THP-1 and AC16. Pathway analysis showed that piR-hsa-23619 was mainly involved in TNF signaling pathway, and piR-hsa-28646 was mainly involved in Wnt signaling pathway. CONCLUSION piR-hsa-9010, piR-hsa-28646, and piR-hsa-23619 were significantly up-regulated in the serum of patients with acute myocardial infarction. It can be used as a new biomarker for the diagnosis of acute myocardial infarction, which may be a therapeutic target for acute myocardial infarction.
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Affiliation(s)
- Ying Huang
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China
| | - Yuan Li
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China
| | - Kaiyu Zhang
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China
| | - Jingyi Xu
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China
| | - Ping Li
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China
| | - Xinxin Yan
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China.
| | - Kangyun Sun
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, PR China.
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25
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Zhong L, Luo Y, Fan J. LncRNAs: Promising Therapeutic Targets and Biomarkers for Ischemic Stroke. Transl Stroke Res 2023; 14:803-805. [PMID: 35691985 DOI: 10.1007/s12975-022-01048-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/06/2022] [Indexed: 10/18/2022]
Abstract
Ischemic stroke is one of the leading causes of mortality and disability worldwide. Currently, options for ischemic stroke clinical therapy remain limited to intravenous thrombolysis and thrombectomy, which can only be applied to a minority of patients due to narrow therapeutic time window. Therefore, the discovery of new therapeutic targets and biomarkers is of great significance for ischemic stroke therapy. Long non-coding RNAs (lncRNAs) are the most extensive ncRNA transcripts and play critical roles in different kinds of diseases. Accumulative evidence suggests that lncRNAs are widely involved in multiple pathophysiological processes of ischemic stroke, highlighting their potential role as ischemic stroke therapeutic targets. Moreover, the significantly altered expression of lncRNAs in circulation of ischemic stroke patients reveals that they may serve as diagnostic, therapeutic, and prognosis biomarkers for ischemic stroke. In this commentary, we provide an overview of the roles of lncRNAs in the pathophysiology of ischemic stroke and discuss the opportunities of lncRNAs in the diagnosis and treatment of ischemic stroke. In addition, the challenges for the clinical translation of lncRNAs in ischemic stroke are also discussed.
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Affiliation(s)
- Liyuan Zhong
- Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China
| | - Yumin Luo
- Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
- Beijing Municipal Geriatric Medical Research Center, Beijing, 100053, China.
- Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100053, China.
| | - Junfen Fan
- Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
- Beijing Municipal Geriatric Medical Research Center, Beijing, 100053, China.
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26
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Rodríguez-Esparragón F, Torres-Mata LB, Cazorla-Rivero SE, Serna Gómez JA, González Martín JM, Cánovas-Molina Á, Medina-Suárez JA, González-Hernández AN, Estupiñán-Quintana L, Bartolomé-Durán MC, Rodríguez-Pérez JC, Varas BC. Analysis of ANRIL Isoforms and Key Genes in Patients with Severe Coronary Artery Disease. Int J Mol Sci 2023; 24:16127. [PMID: 38003316 PMCID: PMC10671206 DOI: 10.3390/ijms242216127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
ANRIL (Antisense Noncoding RNA in the INK4 Locus), also named CDKN2B-AS1, is a long non-coding RNA with outstanding functions that regulates genes involved in atherosclerosis development. ANRIL genotypes and the expression of linear and circular isoforms have been associated with coronary artery disease (CAD). The CDKN2A and the CDKN2B genes at the CDKN2A/B locus encode the Cyclin-Dependent Kinase inhibitor protein (CDKI) p16INK4a and the p53 regulatory protein p14ARF, which are involved in cell cycle regulation, aging, senescence, and apoptosis. Abnormal ANRIL expression regulates vascular endothelial growth factor (VEGF) gene expression, and upregulated Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis by activating the NF-κB signaling pathway. Here, we explored associations between determinations of the linear, circular, and linear-to-circular ANRIL gene expression ratio, CDKN2A, VEGF and its receptor kinase insert domain-containing receptor (KDR) and cardiovascular risk factors and all-cause mortality in high-risk coronary patients before they undergo coronary artery bypass grafting surgery (CABG). We found that the expression of ANRIL isoforms may help in the prediction of CAD outcomes. Linear isoforms were correlated with a worse cardiovascular risk profile while the expression of circular isoforms of ANRIL correlated with a decrease in oxidative stress. However, the determination of the linear versus circular ratio of ANRIL did not report additional information to that determined by the evaluation of individual isoforms. Although the expressions of the VEFG and KDR genes correlated with a decrease in oxidative stress, in binary logistic regression analysis it was observed that only the expression of linear isoforms of ANRIL and VEGF significantly contributed to the prediction of the number of surgical revascularizations.
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Affiliation(s)
- Francisco Rodríguez-Esparragón
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias de la Universidad de La Laguna, 38296 San Cristobal de La Laguna, Tenerife, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Laura B. Torres-Mata
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Department of Specific Didactics, University of Las Palmas de Gran Canaria, 35004 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - Sara E. Cazorla-Rivero
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Department of Internal Medicine, University of La Laguna, 38200 La Laguna, Tenerife, Spain
| | - Jaime A. Serna Gómez
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Deparment of Cardiovascular Surgery, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - Jesús M. González Martín
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ángeles Cánovas-Molina
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Chronic Pain Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - José A. Medina-Suárez
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Department of Specific Didactics, University of Las Palmas de Gran Canaria, 35004 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - Ayose N. González-Hernández
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Deparment of Neurology and Clinical Neurophysiology, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - Lidia Estupiñán-Quintana
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - María C. Bartolomé-Durán
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
| | - José C. Rodríguez-Pérez
- Vice Chancellor of Research, Universidad Fernando Pessoa Canarias, 35002 Santa María de Guía de Gran Canaria, Gran Canaria, Spain;
| | - Bernardino Clavo Varas
- Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain; (L.B.T.-M.); (S.E.C.-R.); (J.A.S.G.); (J.M.G.M.); (Á.C.-M.); (J.A.M.-S.); (A.N.G.-H.); (L.E.-Q.); (M.C.B.-D.)
- Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias de la Universidad de La Laguna, 38296 San Cristobal de La Laguna, Tenerife, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Chronic Pain Unit, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Universitary Institute for Research in Biomedicine and Health (iUIBS), Molecular and Translational Pharmacology Group, University of Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Gran Canaria, Spain
- Spanish Group of Clinical Research in Radiation Oncology (GICOR), 28290 Madrid, Spain
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Xu ZJ, Zhang PY, Li ZQ, Zhu HP, Tan WL, Ren PH. LncRNA AC125982.2 regulates apoptosis of cardiomyocytes through mir-450b-3p/ATG4B axis in a rat model with myocardial infarction. Heliyon 2023; 9:e22467. [PMID: 38074857 PMCID: PMC10700634 DOI: 10.1016/j.heliyon.2023.e22467] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND The occurrence and disability of myocardial infarction (MI) are on the rise globally, making it a significant contributor to cardiovascular mortality. Irreversible myocardial apoptosis plays a crucial role in causing MI. Long non-coding RNAs (LncRNAs) are key regulators of the cardiac remodeling process. Therefore, it is necessary to explore the effect of LncRNAs on cardiomyocyte apoptosis in MI. METHODS The rat-MI model was constructed, LncRNA-Seq and qPCR analyses were used to determine differentially expressed genes obtained from heart tissue of rats in the MI and sham groups. The miRanda software was used to predict the binding sites of LncRNA-miRNA and miRNA-mRNA, which were futhrer verified by dual luciferase assay. The LncRNA-miRNA-apoptosis pathway was further validated using hypoxia-exposed primary cardiomyocytes. RESULTS Compared to the sham group, 412 LncRNAs were upregulated and 501 LncRNAs were downregulated in MI-rat heart tissues. Among them, LncRNA AC125982.2 was most significantly upregulated in MI-rat heart tissues and hypoxic cardiomyocytes. Knockdown of AC125982.2 and ATG4B expression reversed hypoxia-induced apoptosis. In addition, transfection of mir-450b-3p inhibitor attenuated the protective effect of AC125982.2 knockdown. Moreover, we found that AC125982.2 modulated ATG4B expression by acting as a sponge for miR-450b-3p. CONCLUSION Upregulated AC125982.2 expression regulates ATG4B by sponging miR-450b-3p, promoting cardiomyocyte apoptosis and contributing to rat MI development.
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Affiliation(s)
- Zhi-jun Xu
- Guangzhou Medical University, Guangzhou, 511436, China
| | | | - Zhen-qiu Li
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Han-ping Zhu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Wei-lu Tan
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Pei-hua Ren
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
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Bergonzini M, Loreni F, Lio A, Russo M, Saitto G, Cammardella A, Irace F, Tramontin C, Chello M, Lusini M, Nenna A, Ferrisi C, Ranocchi F, Musumeci F. Panoramic on Epigenetics in Coronary Artery Disease and the Approach of Personalized Medicine. Biomedicines 2023; 11:2864. [PMID: 37893238 PMCID: PMC10604795 DOI: 10.3390/biomedicines11102864] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/02/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Epigenetic modifications play a fundamental role in the progression of coronary artery disease (CAD). This panoramic review aims to provide an overview of the current understanding of the epigenetic mechanisms involved in CAD pathogenesis and highlights the potential implications for personalized medicine approaches. Epigenetics is the study of heritable changes that do not influence alterations in the DNA sequence of the genome. It has been shown that epigenetic processes, including DNA/histone methylation, acetylation, and phosphorylation, play an important role. Additionally, miRNAs, lncRNAs, and circRNAs are also involved in epigenetics, regulating gene expression patterns in response to various environmental factors and lifestyle choices. In the context of CAD, epigenetic alterations contribute to the dysregulation of genes involved in inflammation, oxidative stress, lipid metabolism, and vascular function. These epigenetic changes can occur during early developmental stages and persist throughout life, predisposing individuals to an increased risk of CAD. Furthermore, in recent years, the concept of personalized medicine has gained significant attention. Personalized medicine aims to tailor medical interventions based on an individual's unique genetic, epigenetic, environmental, and lifestyle factors. In the context of CAD, understanding the interplay between genetic variants and epigenetic modifications holds promise for the development of more precise diagnostic tools, risk stratification models, and targeted therapies. This review summarizes the current knowledge of epigenetic mechanisms in CAD and discusses the fundamental principles of personalized medicine.
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Affiliation(s)
- Marcello Bergonzini
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Francesco Loreni
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Antonio Lio
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Marco Russo
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Guglielmo Saitto
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Antonio Cammardella
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Francesco Irace
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Corrado Tramontin
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Massimo Chello
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Mario Lusini
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Antonio Nenna
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Chiara Ferrisi
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Federico Ranocchi
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
| | - Francesco Musumeci
- Department of Cardiac Surgery and Heart Transplantation, San Camillo Forlanini Hospital, 00152 Rome, Italy
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Tran T, Cruz C, Chan A, Awad S, Rajasingh J, Deth R, Gurusamy N. Mesenchymal Stem Cell-Derived Long Noncoding RNAs in Cardiac Injury and Repair. Cells 2023; 12:2268. [PMID: 37759491 PMCID: PMC10527806 DOI: 10.3390/cells12182268] [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: 07/16/2023] [Revised: 09/05/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023] Open
Abstract
Cardiac injury, such as myocardial infarction and heart failure, remains a significant global health burden. The limited regenerative capacity of the adult heart poses a challenge for restoring its function after injury. Mesenchymal stem cells (MSCs) have emerged as promising candidates for cardiac regeneration due to their ability to differentiate into various cell types and secrete bioactive molecules. In recent years, attention has been given to noncoding RNAs derived from MSCs, particularly long noncoding RNAs (lncRNAs), and their potential role in cardiac injury and repair. LncRNAs are RNA molecules that do not encode proteins but play critical roles in gene regulation and cellular responses including cardiac repair and regeneration. This review focused on MSC-derived lncRNAs and their implications in cardiac regeneration, including their effects on cardiac function, myocardial remodeling, cardiomyocyte injury, and angiogenesis. Understanding the molecular mechanisms of MSC-derived lncRNAs in cardiac injury and repair may contribute to the development of novel therapeutic strategies for treating cardiovascular diseases. However, further research is needed to fully elucidate the potential of MSC-derived lncRNAs and address the challenges in this field.
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Affiliation(s)
- Talan Tran
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA
| | - Claudia Cruz
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA
| | - Anthony Chan
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA
| | - Salma Awad
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA
| | - Johnson Rajasingh
- Department of Bioscience Research, University of Tennessee Health Science Center, 847 Monroe Avenue, Memphis, TN 38163, USA
| | - Richard Deth
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA
| | - Narasimman Gurusamy
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA
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Yu X. Promising Therapeutic Treatments for Cardiac Fibrosis: Herbal Plants and Their Extracts. Cardiol Ther 2023; 12:415-443. [PMID: 37247171 PMCID: PMC10423196 DOI: 10.1007/s40119-023-00319-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/27/2023] [Indexed: 05/30/2023] Open
Abstract
Cardiac fibrosis is closely associated with multiple heart diseases, which are a prominent health issue in the global world. Neurohormones and cytokines play indispensable roles in cardiac fibrosis. Many signaling pathways participate in cardiac fibrosis as well. Cardiac fibrosis is due to impaired degradation of collagen and impaired fibroblast activation, and collagen accumulation results in increasing heart stiffness and inharmonious activity, leading to structure alterations and finally cardiac function decline. Herbal plants have been applied in traditional medicines for thousands of years. Because of their naturality, they have attracted much attention for use in resisting cardiac fibrosis in recent years. This review sheds light on several extracts from herbal plants, which are promising therapeutics for reversing cardiac fibrosis.
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Affiliation(s)
- Xuejing Yu
- Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75235, USA.
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31
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Jiang Y, Zhao Y, Li ZY, Chen S, Fang F, Cai JH. Potential roles of microRNAs and long noncoding RNAs as diagnostic, prognostic and therapeutic biomarkers in coronary artery disease. Int J Cardiol 2023; 384:90-99. [PMID: 37019219 DOI: 10.1016/j.ijcard.2023.03.067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/27/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023]
Abstract
Coronary artery disease (CAD), which is mainly caused by atherosclerotic processes in coronary arteries, became a significant health issue. MicroRNAs (miRNAs), and long noncoding RNAs (lncRNAs), have been shown to be stable in plasma and could thereby be adopted as biomarkers for CAD diagnosis and treatment. MiRNAs can regulate CAD development through different pathways and mechanisms, including modulation of vascular smooth muscle cell (VSMC) activity, inflammatory responses, myocardial injury, angiogenesis, and leukocyte adhesion. Similarly, previous studies have indicated that the causal effects of lncRNAs in CAD pathogenesis and their utility in CAD diagnosis and treatment, has been found to lead to cell cycle transition, proliferation dysregulation, and migration in favour of CAD development. Differential expression of miRNAs and lncRNAs in CAD patients has been identified and served as diagnostic, prognostic and therapeutic biomarkers for the assessment of CAD patients. Thus, in the current review, we summarize the functions of miRNAs and lncRNAs, which aimed to identify novel targets for the CAD diagnosis, prognosis, and treatment.
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Affiliation(s)
- Yong Jiang
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China.
| | - Ying Zhao
- Department of Cardiology, Jilin Central Hospital, Jilin 132011, China
| | - Zheng-Yi Li
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China
| | - Shuang Chen
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China
| | - Fang Fang
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China.
| | - Jian-Hui Cai
- Department of Clinical Medicine, Jilin Medical University, Jilin 132013, China; Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University, Jilin 132013, China.
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Dave J, Jagana V, Janostiak R, Bisserier M. Unraveling the epigenetic landscape of pulmonary arterial hypertension: implications for personalized medicine development. J Transl Med 2023; 21:477. [PMID: 37461108 DOI: 10.1186/s12967-023-04339-5] [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] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/10/2023] [Indexed: 07/20/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a multifactorial disease associated with the remodeling of pulmonary blood vessels. If left unaddressed, PAH can lead to right heart failure and even death. Multiple biological processes, such as smooth muscle proliferation, endothelial dysfunction, inflammation, and resistance to apoptosis, are associated with PAH. Increasing evidence suggests that epigenetic factors play an important role in PAH by regulating the chromatin structure and altering the expression of critical genes. For example, aberrant DNA methylation and histone modifications such as histone acetylation and methylation have been observed in patients with PAH and are linked to vascular remodeling and pulmonary vascular dysfunction. In this review article, we provide a comprehensive overview of the role of key epigenetic targets in PAH pathogenesis, including DNA methyltransferase (DNMT), ten-eleven translocation enzymes (TET), switch-independent 3A (SIN3A), enhancer of zeste homolog 2 (EZH2), histone deacetylase (HDAC), and bromodomain-containing protein 4 (BRD4). Finally, we discuss the potential of multi-omics integration to better understand the molecular signature and profile of PAH patients and how this approach can help identify personalized treatment approaches.
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Affiliation(s)
- Jaydev Dave
- Department of Cell Biology and Anatomy, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY, 10595, USA
- Department of Physiology, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY, 10595, USA
| | - Vineeta Jagana
- Department of Cell Biology and Anatomy, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY, 10595, USA
- Department of Physiology, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY, 10595, USA
| | - Radoslav Janostiak
- First Faculty of Medicine, BIOCEV, Charles University, Vestec, 25250, Czech Republic
| | - Malik Bisserier
- Department of Cell Biology and Anatomy, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY, 10595, USA.
- Department of Physiology, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY, 10595, USA.
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Zhang F, Shi H, Xue H, Li H, Li C, Han Q. Up-regulated lncRNA SNHG9 mediates the pathogenesis of dilated cardiomyopathy via miR-326/EPHB3 axis. J Thromb Thrombolysis 2023; 55:634-648. [PMID: 37004604 DOI: 10.1007/s11239-023-02798-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/15/2023] [Indexed: 04/04/2023]
Abstract
Dilated cardiomyopathy (DCM) is a common cause of heart failure and also a major indication for heart transplantation. It has been reported that long non-coding RNAs (lncRNAs) are involved in the development of various cardiac diseases. However, the roles of lncRNAs in DCM are not fully understood. In this study, we uncovered that serum SNHG9 (small nucleolar RNA host gene 9, a lncRNA) serves as a biomarker for dilated cardiomyopathy. GEO datasets (GSE124405) were re-analyzed to identify the aberrant lncRNAs in the plasma sample of patients with heart failure. The receiver operating characteristic (ROC) curve was used to assess the expression alterations of the aberrant lncRNAs including SNHG9, XIST, PLCK2-AS1, KIF9-AS1, ARHGAP31-AS1, LINC00482, etc. Using the area under curve (AUC) of ROC, we found that serum SNHG9 exhibits considerable performance in distinguishing DCM from normal control and DCM stage-III from stage-I/II (New York Heart Association Class). Furthermore, we determined the serum SNHG9 expression level of the doxorubicin (Dox)-induced DCM mice model, and found that the upregulated SNHG9 is negatively associated with heart function. Besides, the deletion of SNHG9 by AAV-9 alleviated heart injury in the Dox-induced mice model. Taken together, the current results suggest that SNHG9 is a novel regulatory factor in dilated cardiomyopathy development.
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Affiliation(s)
- Fan Zhang
- Department of Cardiology, the First Hospital of Shanxi Medical University, 85 South Jiefang Road, Taiyuan, Shanxi Province, 030001, People's Republic of China
- Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Hongtao Shi
- Department of Cardiology, the First Hospital of Shanxi Medical University, 85 South Jiefang Road, Taiyuan, Shanxi Province, 030001, People's Republic of China
| | - Honghong Xue
- Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Hao Li
- Department of Cardiology, the First Hospital of Shanxi Medical University, 85 South Jiefang Road, Taiyuan, Shanxi Province, 030001, People's Republic of China
| | - Chao Li
- Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Qinghua Han
- Department of Cardiology, the First Hospital of Shanxi Medical University, 85 South Jiefang Road, Taiyuan, Shanxi Province, 030001, People's Republic of China.
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Loganathan T, Doss C GP. Non-coding RNAs in human health and disease: potential function as biomarkers and therapeutic targets. Funct Integr Genomics 2023; 23:33. [PMID: 36625940 PMCID: PMC9838419 DOI: 10.1007/s10142-022-00947-4] [Citation(s) in RCA: 84] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 01/11/2023]
Abstract
Human diseases have been a critical threat from the beginning of human history. Knowing the origin, course of action and treatment of any disease state is essential. A microscopic approach to the molecular field is a more coherent and accurate way to explore the mechanism, progression, and therapy with the introduction and evolution of technology than a macroscopic approach. Non-coding RNAs (ncRNAs) play increasingly important roles in detecting, developing, and treating all abnormalities related to physiology, pathology, genetics, epigenetics, cancer, and developmental diseases. Noncoding RNAs are becoming increasingly crucial as powerful, multipurpose regulators of all biological processes. Parallel to this, a rising amount of scientific information has revealed links between abnormal noncoding RNA expression and human disorders. Numerous non-coding transcripts with unknown functions have been found in addition to advancements in RNA-sequencing methods. Non-coding linear RNAs come in a variety of forms, including circular RNAs with a continuous closed loop (circRNA), long non-coding RNAs (lncRNA), and microRNAs (miRNA). This comprises specific information on their biogenesis, mode of action, physiological function, and significance concerning disease (such as cancer or cardiovascular diseases and others). This study review focuses on non-coding RNA as specific biomarkers and novel therapeutic targets.
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Affiliation(s)
- Tamizhini Loganathan
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore- 632014, Tamil Nadu, India
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore- 632014, Tamil Nadu, India.
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MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β 1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome. Cell Death Dis 2022; 8:504. [PMID: 36585403 PMCID: PMC9803679 DOI: 10.1038/s41420-022-01295-9] [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: 09/19/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022]
Abstract
The β1-adrenergic receptor (β1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of β-arrestin-mediated β1AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant β1AR (G protein-coupled receptor kinase [GRK]-β1AR that exhibits impairment in β-arrestin-mediated β1AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK-β1AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of β1AR/β-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to β1AR/β-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.
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Sumaiya K, Ponnusamy T, Natarajaseenivasan K, Shanmughapriya S. Cardiac Metabolism and MiRNA Interference. Int J Mol Sci 2022; 24:50. [PMID: 36613495 PMCID: PMC9820363 DOI: 10.3390/ijms24010050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
The aberrant increase in cardio-metabolic diseases over the past couple of decades has drawn researchers' attention to explore and unveil the novel mechanisms implicated in cardiometabolic diseases. Recent evidence disclosed that the derangement of cardiac energy substrate metabolism plays a predominant role in the development and progression of chronic cardiometabolic diseases. Hence, in-depth comprehension of the novel molecular mechanisms behind impaired cardiac metabolism-mediated diseases is crucial to expand treatment strategies. The complex and dynamic pathways of cardiac metabolism are systematically controlled by the novel executor, microRNAs (miRNAs). miRNAs regulate target gene expression by either mRNA degradation or translational repression through base pairing between miRNA and the target transcript, precisely at the 3' seed sequence and conserved heptametrical sequence in the 5' end, respectively. Multiple miRNAs are involved throughout every cardiac energy substrate metabolism and play a differential role based on the variety of target transcripts. Novel theoretical strategies have even entered the clinical phase for treating cardiometabolic diseases, but experimental evidence remains inadequate. In this review, we identify the potent miRNAs, their direct target transcripts, and discuss the remodeling of cardiac metabolism to cast light on further clinical studies and further the expansion of novel therapeutic strategies. This review is categorized into four sections which encompass (i) a review of the fundamental mechanism of cardiac metabolism, (ii) a divulgence of the regulatory role of specific miRNAs on cardiac metabolic pathways, (iii) an understanding of the association between miRNA and impaired cardiac metabolism, and (iv) summary of available miRNA targeting therapeutic approaches.
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Affiliation(s)
- Krishnamoorthi Sumaiya
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India
| | - Thiruvelselvan Ponnusamy
- Department of Medicine, Department of Cellular and Molecular Physiology, Heart and Vascular Institute, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Department of Medicine, Department of Cellular and Molecular Physiology, Heart and Vascular Institute, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
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Zhang M, Zhang B, Wang X, Song J, Tong M, Dong Z, Xu J, Liu M, Jiang Y, Wang N, Wang Y, Du Z, Liu Y, Zhang R, Xu C. LncRNA CFAR promotes cardiac fibrosis via the miR-449a-5p/LOXL3/mTOR axis. SCIENCE CHINA LIFE SCIENCES 2022; 66:783-799. [PMID: 36334219 DOI: 10.1007/s11427-021-2132-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/22/2022] [Indexed: 11/06/2022]
Abstract
Cardiac fibrosis is one of the crucial pathological factors in the heart, and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure. However, the exact molecular mechanism of cardiac fibrosis remains unclear. In the present study, we show that a novel lncRNA that we named cardiac fibrosis-associated regulator (CFAR) is a profibrotic factor in the heart. CFAR was upregulated in cardiac fibrosis and its knockdown attenuated the expression of fibrotic marker genes and the proliferation of cardiac fibroblasts, thereby ameliorating cardiac fibrosis. Moreover, CFAR acted as a ceRNA sponge for miR-449a-5p and derepressed the expression of LOXL3, which we experimentally established as a target gene of miR-449a-5p. In contrast to CFAR, miR-449a-5p was found to be significantly downregulated in cardiac fibrosis, and artificial knockdown of miR-449a-5p exacerbated fibrogenesis, whereas overexpression of miR-449a-5p impeded fibrogenesis. Furthermore, we found that LOXL3 mimicked the fibrotic factor TGF-β1 to promote cardiac fibrosis by activating mTOR. Collectively, our study established CFAR as a new profibrotic factor acting through a novel miR-449a-5p/LOXL3/mTOR axis in the heart and therefore might be considered as a potential molecular target for the treatment of cardiac fibrosis and associated heart diseases.
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Affiliation(s)
- Mingyu Zhang
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Bowen Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Xiaohan Wang
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Jiahang Song
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Ming Tong
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Zheng Dong
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Jiaonan Xu
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Meng Liu
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yuan Jiang
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Ning Wang
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Ying Wang
- Center of Chronic Diseases and Drug Research of Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Zhimin Du
- Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Yanyan Liu
- Zhuhai People's Hospital, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China.
| | - Rong Zhang
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
| | - Chaoqian Xu
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
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Ma J, Lei P, Chen H, Wang L, Fang Y, Yan X, Yang Q, Peng B, Jin L, Sun D. Advances in lncRNAs from stem cell-derived exosome for the treatment of cardiovascular diseases. Front Pharmacol 2022; 13:986683. [PMID: 36147326 PMCID: PMC9486024 DOI: 10.3389/fphar.2022.986683] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/12/2022] [Indexed: 11/21/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality globally. Benefiting from the advantages of early diagnosis and precision medicine, stem cell-based therapies have emerged as promising treatment options for CVDs. However, autologous or allogeneic stem cell transplantation imposes a potential risk of immunological rejection, infusion toxicity, and oncogenesis. Fortunately, exosome can override these limitations. Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) in exosome from stem cell paracrine factors play critical roles in stem cell therapy and participate in numerous regulatory processes, including transcriptional silencing, transcriptional activation, chromosome modification, and intranuclear transport. Accordingly, lncRNAs can treat CVDs by directly acting on specific signaling pathways. This mini review systematically summarizes the key regulatory actions of lncRNAs from different stem cells on myocardial aging and apoptosis, ischemia-reperfusion injury, retinopathy, atherosclerosis, and hypertension. In addition, the current challenges and future prospects of lncRNAs treatment for CVDs are discussed.
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Affiliation(s)
- Jiahui Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Pengyu Lei
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Haojie Chen
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Lei Wang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Yimeng Fang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Xiaoqing Yan
- Department of Pharmacy, Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Bo Peng
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Libo Jin
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
- *Correspondence: Da Sun, ; Libo Jin,
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
- *Correspondence: Da Sun, ; Libo Jin,
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Elbaz M, Faccini J, Laperche C, Grazide MH, Ruidavets JB, Vindis C. MiR-223 and MiR-186 Are Associated with Long-Term Mortality after Myocardial Infarction. Biomolecules 2022; 12:biom12091243. [PMID: 36139082 PMCID: PMC9496068 DOI: 10.3390/biom12091243] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/28/2022] Open
Abstract
Background—The identification and stratification of patients at risk of fatal outcomes after myocardial infarction (MI) is of considerable interest to guide secondary prevention therapies. Currently, no accurate biomarkers are available to identify subjects who are at risk of suffering acute manifestations of coronary heart disease as well as to predict adverse events after MI. Non-coding circulating microRNAs (miRNAs) have been proposed as novel diagnostic and prognostic biomarkers in cardiovascular diseases. The aims of the study were to investigate the clinical value of a panel of circulating miRNAs as accurate biomarkers associated with MI and mortality risk prediction in patients with documented MI. Methods and Results—seven circulating plasma miRNAs were analyzed in 67 MI patients and 80 control subjects at a high cardiovascular risk but without known coronary diseases. Multivariate logistic regression analyses demonstrated that six miRNAs were independently associated with MI occurrence. Among them, miR-223 and miR-186 reliably predicted long-term mortality in MI patients, in particular miR-223 (HR 1.57 per one-unit increase, p = 0.02), after left ventricular ejection fraction (LVEF) adjustment. Kaplan–Meier survival analyses provided a predictive threshold value of miR-223 expression (p = 0.028) for long-term mortality. Conclusions—Circulating miR-223 and miR-186 are promising predictive biomarkers for long-term mortality after MI.
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Affiliation(s)
- Meyer Elbaz
- Department of Cardiology, Rangueil University Hospital, 31400 Toulouse, France
- Center for Clinical Investigation (CIC1436)/CARDIOMET, Rangueil University Hospital, 31400 Toulouse, France
- INSERM UMR 1048, 31400 Toulouse, France
| | | | - Clémence Laperche
- Department of Cardiology, Rangueil University Hospital, 31400 Toulouse, France
- INSERM UMR 1048, 31400 Toulouse, France
| | - Marie-Hélène Grazide
- Center for Clinical Investigation (CIC1436)/CARDIOMET, Rangueil University Hospital, 31400 Toulouse, France
- INSERM UMR 1048, 31400 Toulouse, France
| | | | - Cécile Vindis
- Center for Clinical Investigation (CIC1436)/CARDIOMET, Rangueil University Hospital, 31400 Toulouse, France
- INSERM UMR 1048, 31400 Toulouse, France
- Correspondence:
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Yin X, Wang M, Wang W, Chen T, Song G, Niu Y, Jiang Z, Gao Z, Wang Z. Identification of Potential miRNA-mRNA Regulatory Network Contributing to Parkinson's Disease. PARKINSON'S DISEASE 2022; 2022:2877728. [PMID: 36105301 PMCID: PMC9467752 DOI: 10.1155/2022/2877728] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/02/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease, and the mechanism underlying PD pathogenesis is not completely understood. Increasing evidence indicates that microRNAs (miRNAs) play a critical regulatory role in the pathogenesis of PD. This study aimed to explore the miRNA-mRNA regulatory network for PD. The differentially expressed miRNAs (DEmis) and genes (DEGs) between PD patients and healthy donors were screened from the miRNA dataset GSE16658 and mRNA dataset GSE100054 downloaded from the Gene Expression Omnibus (GEO) database. Target genes of the DEmis were selected when they were predicted by three or four online databases and overlapped with DEGs from GSE100054. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then conducted by Database for Annotation, Visualization and Integrated Discovery (DAVID) and Metascape analytic tools. The correlation between the screened genes and PD was evaluated with the online tool Comparative Toxicogenomics Database (CTD), and protein-protein interaction (PPI) networks were built by the STRING platform. We further investigated the expression of genes in the miRNA-mRNA regulatory network in blood samples collected from PD patients and healthy donors via qRT-PCR. We identified 1505 upregulated and 1302 downregulated DEGs, and 77 upregulated and 112 downregulated DEmis were preliminarily screened from the GEO database. Further functional enrichment analysis identified 10 PD-related hub genes, including RAC1, IRS2, LEPR, PPARGC1A, CAMKK2, RAB10, RAB13, RAB27B, RAB11A, and JAK2, which were mainly involved in Rab protein signaling transduction, AMPK signaling pathway, and signaling by Leptin. A miRNA-mRNA regulatory network was then constructed with 10 hub genes, and their interacting miRNAs overlapped with DEmis, including miR-30e-5p, miR-142-3p, miR-101-3p, miR-32-3p, miR-508-5p, miR-642a-5p, miR-19a-3p, and miR-21-5p. Analysis of clinical samples verified significant upregulation of LEPR and downregulation of miR-101-3p and miR-30e-5p in PD patients as compared with healthy donors. Thus, the miRNA-mRNA regulatory network was initially constructed and has the potential to provide novel insights into the pathogenesis and treatment of PD.
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Affiliation(s)
- Xi Yin
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Miao Wang
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Wei Wang
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Tong Chen
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Ge Song
- Department of Geriatrics, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Yixuan Niu
- Department of Geriatrics, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Ziying Jiang
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Zhongbao Gao
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Zhenfu Wang
- Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
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Liu TY, Feng H, Yousuf S, Xie LL, Miao XY. Genome-Wide Analysis of microRNAs Identifies the Lipid Metabolism Pathway to Be a Defining Factor in Adipose Tissue From Different Sheep. Front Vet Sci 2022; 9:938311. [PMID: 35880040 PMCID: PMC9308008 DOI: 10.3389/fvets.2022.938311] [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: 05/07/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
microRNAs are a class of important non-coding RNAs, which can participate in the regulation of biological processes. In recent years, miRNA has been widely studied not only in humans and mice, but also in animal husbandry. However, compared with other livestock and poultry breeds, the study of miRNA in subcutaneous adipose tissue of sheep is not comprehensive. Transcriptome analysis of miRNAs in subcutaneous adipose tissue of Duolang sheep, and Small Tail Han sheep was performed using RNA-Seq technology. Differentially expressed miRNAs were screened between different breeds. Target genes were predicted, and then the joint analysis of candidate genes were conducted based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the RNA-Seq data were verified by real-time quantitative polymerase chain reaction (qRT-PCR). Herein, we identified 38 differentially expressed miRNAs (9 novel miRNAs and 29 known miRNAs). In addition, a total of 854 target genes were predicted by miRanda software. GO and KEGG pathway analysis demonstrated that regulation of lipolysis in adipocytes plays a key role in the deposition of subcutaneous adipose tissue in Duolang sheep and Small Tail Han sheep. The miRNAs might regulate fat deposits by regulating genes involved in regulation of lipolysis in adipocytes. Specifically, NC_ 040278.1_ 37602, oar-mir-493-3p, NC_ 040278.1_ 37521 and NC_ 040255.1_ 11627 might target PTGS2, AKT2, AKT3, and PIK3CA, respectively, and then play critical regulatory role. In conclusion, all the results provide a good idea for further revealing the mechanism of subcutaneous adipose tissue deposition and improving the meat production performance of sheep, and lay a foundation for promoting the development of animal husbandry.
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Fan J, Ren M, He Y. Diagnostic and Therapeutic Properties of Exosomes in Cardiac Fibrosis. Front Cell Dev Biol 2022; 10:931082. [PMID: 35859903 PMCID: PMC9289295 DOI: 10.3389/fcell.2022.931082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiac fibrosis results from both the differentiation of cardiac fibroblasts and excessive accumulation of extracellular matrix (ECM), leading to myocardial stiffness and reduced compliance of the ventricular wall. The conversion of cardiac fibroblasts to myofibroblasts is the most important initiating step in the process of this pathological cardiac remodeling. It occurs during the progression of many cardiovascular diseases, adversely influencing both the clinical course and outcome of the disease. The pathogenesis is complex and there is no effective treatment. Exosomes are extracellular vesicles that mediate intercellular communication through delivering specific cargoes of functional nucleic acids and proteins derived from particular cell types. Recent studies have found that exosomes play an important role in the diagnosis and treatment of cardiac fibrosis, and is a potential biotherapeutics and drug delivery vectors for the treatment of cardiac fibrosis. The present review aimed to summarize the current knowledge of exosome-related mechanisms underlying cardiac fibrosis and to suggest potential therapy that could be used to treat the condition.
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Affiliation(s)
- Jiwen Fan
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meng Ren
- Department of Medical Oncology, Jilin Provincial Cancer Hospital, Changchun, China
| | - Yuquan He
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Yuquan He,
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Raafs AG, Vos JL, Henkens MTHM, Slurink BO, Verdonschot JAJ, Bossers D, Roes K, Gerretsen S, Knackstedt C, Hazebroek MR, Nijveldt R, Heymans SRB. Left Atrial Strain Has Superior Prognostic Value to Ventricular Function and Delayed-Enhancement in Dilated Cardiomyopathy. JACC Cardiovasc Imaging 2022; 15:1015-1026. [PMID: 35680209 DOI: 10.1016/j.jcmg.2022.01.016] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/01/2022] [Accepted: 01/24/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND The left atrium is an early sensor of left ventricular (LV) dysfunction. Still, the prognostic value of left atrial (LA) function (strain) on cardiac magnetic resonance (CMR) in dilated cardiomyopathy (DCM) remains unknown. OBJECTIVES The goal of this study was to evaluate the prognostic value of CMR-derived LA strain in DCM. METHODS Patients with DCM from the Maastricht Cardiomyopathy Registry with available CMR imaging were included. The primary endpoint was the combination of sudden or cardiac death, heart failure (HF) hospitalization, or life-threatening arrhythmias. Given the nonlinearity of continuous variables, cubic spline analysis was performed to dichotomize. RESULTS A total of 488 patients with DCM were included (median age: 54 [IQR: 46-62] years; 61% male). Seventy patients (14%) reached the primary endpoint (median follow-up: 6 [IQR: 4-9] years). Age, New York Heart Association (NYHA) functional class >II, presence of late gadolinium enhancement (LGE), LV ejection fraction (LVEF), LA volume index (LAVI), LV global longitudinal strain (GLS), and LA reservoir and conduit strain were univariably associated with the outcome (all P < 0.02). LA conduit strain was a stronger predictor of outcome compared with reservoir strain. LA conduit strain, NYHA functional class >II, and LGE remained associated in the multivariable model (LA conduit strain HR: 3.65 [95% CI: 2.01-6.64; P < 0.001]; NYHA functional class >II HR: 1.81 [95% CI: 1.05-3.12; P = 0.033]; and LGE HR: 2.33 [95% CI: 1.42-3.85; P < 0.001]), whereas age, N-terminal pro-B-type natriuretic peptide, LVEF, left atrial ejection fraction, LAVI, and LV GLS were not. Adding LA conduit strain to other independent predictors (NYHA functional class and LGE) significantly improved the calibration, accuracy, and reclassification of the prediction model (P < 0.05). CONCLUSIONS LA conduit strain on CMR is a strong independent prognostic predictor in DCM, superior to LV GLS, LVEF, and LAVI and incremental to LGE. Including LA conduit strain in DCM patient management should be considered to improve risk stratification.
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Affiliation(s)
- Anne G Raafs
- Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
| | - Jacqueline L Vos
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Michiel T H M Henkens
- Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands; Netherlands Heart Institute (NLHI), Utrecht, the Netherlands
| | - Bram O Slurink
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Job A J Verdonschot
- Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Daan Bossers
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Kit Roes
- Department of Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Suzanne Gerretsen
- Department of Radiology and Nuclear Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Christian Knackstedt
- Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
| | - Mark R Hazebroek
- Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
| | - Robin Nijveldt
- Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Stephane R B Heymans
- Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands; Department of Cardiovascular Research, University of Leuven, Leuven, Belgium
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Tonry C, Russel-Hallinan A, McCune C, Collier P, Harbinson M, Dixon L, Watson CJ. Circulating biomarkers for management of cancer therapeutics related cardiac dysfunction. Cardiovasc Res 2022; 119:710-728. [PMID: 35640873 PMCID: PMC10153425 DOI: 10.1093/cvr/cvac087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 05/09/2022] [Accepted: 05/15/2022] [Indexed: 11/14/2022] Open
Abstract
Cancer therapeutics related cardiac dysfunction (CTRCD) has emerged as a major cause of morbidity and mortality in cancer survivors. Effective clinical management of CTRCD is impeded by a lack of sensitive diagnostic and prognostic strategies. Circulating molecular markers could potentially address this need as they are often indicative of cardiac stress before cardiac damage can be detected clinically. A growing understanding of the underlying physiological mechanisms for CTRCD has inspired research efforts to identify novel pathophysiologically-relevant biomarkers that may also guide development of cardio-protective therapeutic approaches. The purpose of this review is to evaluate current circulating biomarkers of cardiac stress and their potential role in diagnosis and management of CTRCD. We also discuss some emerging avenues for CTRCD-focused biomarker investigations.
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Affiliation(s)
- Claire Tonry
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| | - Adam Russel-Hallinan
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| | - Claire McCune
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| | | | | | | | - Chris J Watson
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
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The ceRNA Crosstalk between mRNAs and lncRNAs in Diabetes Myocardial Infarction. DISEASE MARKERS 2022; 2022:4283534. [PMID: 35592708 PMCID: PMC9112177 DOI: 10.1155/2022/4283534] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 04/21/2022] [Indexed: 11/28/2022]
Abstract
Competitive endogenous RNA regulation suggests an intricate network of all transcriptional RNAs that have the function of repressing miRNA function and regulating mRNA expression. Today, the specific ceRNA regulatory mechanisms of lncRNA–miRNA–mRNA in patients who have diabetes mellitus (DM) and myocardial infarction (MI) are still unknown. Two data sets, GSE34198 and GSE112690, were rooted in the Gene Expression Omnibus database to search for changes of lncRNA, miRNA, and mRNA in MI patients with diabetes. Weighted gene correlation network analysis (WGCNA) was used to identify the modules related to the development of diabetes in patients with MI. Target genes of miRNAs were predicted using miRWalk, TargetScan, mirDB, RNA22, and miRanda. Then, functional and enrichment analyses were performed to build the lncRNA–miRNA–mRNA interaction network. We built ceRNA regulatory networks with three lncRNAs, two miRNAs, and nine mRNAs. Differentially expressed genes enriched in biological process, including neutrophil activation, refer to immune response and positive system of defense feedback. Besides, there is significant enrichment in molecular function of calcium toll−like receptor binding, icosanoid binding, RAGE receptor binding, and arachidonic acid binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis enriched differentially expressed genes (DEGs) in pathways that were well known in MI, indicating inflammation and immune response. Pathways associated with diabetes were also significantly enriched. We confirmed significantly altered lncRNA, miRNA, and mRNA in MI patients with diabetes, which might serve as biomarkers for the progress and development of diabetic cardiovascular diseases. We constructed a ceRNA regulatory network of lncRNA–miRNA–mRNA, which will enable us to understand the novel molecular mechanisms included in the initiation, progression, and interaction between DM and MI, laying the foundation for clinical diagnosis and treatment.
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Raggi F, Rossi C, Faita F, Distaso M, Kusmic C, Solini A. P2X7 Receptor and Heart Function in a Mouse Model of Systemic Inflammation Due to High Fat Diet. J Inflamm Res 2022; 15:2425-2439. [PMID: 35444452 PMCID: PMC9015053 DOI: 10.2147/jir.s356038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/09/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Low-grade inflammation contributes to heart failure in obesity or type 2 diabetes mellitus. The P2X7 receptor (P2X7R) is a key regulator of several pro-inflammatory responses in multiple tissues and organs; however, its involvement in the onset of heart dysfunction remains unclear. The study evaluated the role of P2X7R as a cardiac function regulator in C57BL/6J wild-type (WT) and P2X7R knockout (KO) mice by inducing systemic inflammation with high fat diet (HFD). Methods Specific parameters of systolic and diastolic function and heart morphology were measured in vivo before animal sacrifice by high-frequency ultrasonographic analysis. Gene and protein expression of cardiac biomarkers associated with inflammatory-oxidative pathways were evaluated by real-time PCR and Western Blotting. Results P2X7R-mediated up-regulation of the NLRP3-caspase-1 complex, increased expression of key oxidative stress (NOS-2, TNFα), and chemotactic (MCP-1) mediators were revealed in WT-HFD animals. In KO-HFD mice, such inflammatory-oxidative pathway was silent. Nevertheless, HFD induced in vivo a clear alteration of diastolic pattern (E/A: p < 0.03 vs WT-HFD) and a cardiac morphologic remodelling (left ventricular mass: p < 0.05 vs WT-HFD) only in P2X7R KO animals. Surprisingly, the transcriptional and protein expression of IL-1β and IL-6, usually regulated through P2X7R activation, were significantly higher in KO-HFD than in WT-HFD mice (both p < 0.05). Furthermore, an up-regulation of miR-214 and a down-regulation of miR-126 in heart of HFD-KO mice were observed, suggesting a link between such epigenetic dysregulation and cytokine overexpression as a potential pathophysiologic mechanism concurring to the progressive cardiac dysfunction. Conclusion These findings seem to suggest a cardioprotective role of P2X7R toward this tissue-specific inflammatory damage, likely through tissue homeostasis and organ functionality preservation.
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Affiliation(s)
- Francesco Raggi
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Chiara Rossi
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Francesco Faita
- Institute of Clinical Physiology, Italian National Research Council, Pisa, Italy
| | - Mariarosaria Distaso
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Claudia Kusmic
- Institute of Clinical Physiology, Italian National Research Council, Pisa, Italy
| | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
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Aonuma T, Moukette B, Kawaguchi S, Barupala NP, Sepúlveda MN, Frick K, Tang Y, Guglin M, Raman SV, Cai C, Liangpunsakul S, Nakagawa S, Kim IM. MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4. Circ Heart Fail 2022; 15:e008686. [PMID: 35000421 PMCID: PMC9018469 DOI: 10.1161/circheartfailure.121.008686] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction-associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive. METHODS We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. RESULTS Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4. CONCLUSIONS Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.
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Affiliation(s)
- Tatsuya Aonuma
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Bruno Moukette
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Satoshi Kawaguchi
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nipuni P. Barupala
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Marisa N. Sepúlveda
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kyle Frick
- Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yaoliang Tang
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Maya Guglin
- Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Subha V. Raman
- Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chenleng Cai
- Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA;,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Shinichi Nakagawa
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Il-man Kim
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA;,Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA;,Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA;,Address for correspondence: Il-man Kim, PhD, Associate Professor, Department of Anatomy, Cell Biology and Physiology, Wells Center for Pediatric Research, Krannert Institute of Cardiology, Indiana University School of Medicine, 635 Barnhill Drive, MS 346A, Indianapolis, IN 46202, USA, , Phone: 317-278-2086
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Del Toro R, Galeano-Otero I, Bevilacqua E, Guerrero-Márquez F, Falcon D, Guisado-Rasco A, Díaz-de la Llera L, Barón-Esquivias G, Smani T, Ordóñez-Fernández A. Predicted Value of MicroRNAs, Vascular Endothelial Growth Factor, and Intermediate Monocytes in the Left Adverse Ventricular Remodeling in Revascularized ST-Segment Elevation Myocardial Infarction Patients. Front Cardiovasc Med 2022; 9:777717. [PMID: 35402537 PMCID: PMC8987717 DOI: 10.3389/fcvm.2022.777717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/22/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundPrimary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction (STEMI) improves the survival of patients; nevertheless, some patients develop left ventricular adverse remodeling (LVAR) a few months after the intervention. The main objective of this study was to characterize the role of pro-inflammatory cell populations, related cytokines, and microRNAs (miRNAs) released after PPCI as reliable prognostic biomarkers for LVAR in patients with STEMI.MethodsWe evaluated the level of pro-inflammatory subsets, before and after revascularization, 1 and 6 months after PPCI, using flow cytometry. We also performed a miRNA microarray in isolated peripheral blood mononuclear cells (PBMCs) and examined the levels of 27 cytokines in patients’ serum of patients by multiplex ELISA.ResultsWe observed that the levels of classical and intermediate monocytes increased 6 h after PPCI in patients who developed LVAR later. Multivariate regression analysis and ROC curves indicated that intermediate monocytes, after PPCI, were the best monocyte subset that correlated with LVAR. Within the 27 evaluated cytokines evaluated, we found that the increase in the level of vascular endothelial growth factor (VEGF) correlated with LVAR. Furthermore, the microarray analysis of PBMCs determined that up to 1,209 miRNAs were differentially expressed 6 h after PPCI in LVAR patients, compared with those who did not develop LVAR. Using RT-qPCR we confirmed a significant increase in miR-16, miR-21-5p, and miR-29a-3p, suggested to modulate the expression of different cytokines, 6 h post-PPCI in LVAR patients. Interestingly, we determined that the combined analysis of the levels of the intermediate monocyte subpopulation, VEGF, and miRNAs gave a better association with LVAR appearance. Similarly, combined ROC analysis provided high accurate specificity and sensibility to identify STEMI patients who will develop LVAR.ConclusionOur data suggest that the combined analysis of intermediate monocytes, VEGF, and miRNAs predicts LVAR in STEMI patients.
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Affiliation(s)
- Raquel Del Toro
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
- *Correspondence: Raquel Del Toro,
| | - Isabel Galeano-Otero
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
| | - Elisa Bevilacqua
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
| | | | - Debora Falcon
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
| | | | | | - Gonzalo Barón-Esquivias
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
- Servicio de Cardiología, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Tarik Smani
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
- Tarik Smani,
| | - Antonio Ordóñez-Fernández
- Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla-IBiS, Universidad de Sevilla/HUVR/Junta de Andalucía/CSIC, Seville, Spain
- Antonio Ordóñez-Fernández,
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Nenna A, Loreni F, Giacinto O, Chello C, Nappi P, Chello M, Nappi F. miRNAs in Cardiac Myxoma: New Pathologic Findings for Potential Therapeutic Opportunities. Int J Mol Sci 2022; 23:ijms23063309. [PMID: 35328730 PMCID: PMC8954653 DOI: 10.3390/ijms23063309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/13/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, contributing to all major cellular processes. The importance of miRNAs in cardiac development, heart function, and valvular heart disease has been shown in recent years, and aberrant expression of miRNA has been reported in various malignancies, such as gastric cancer and breast cancer. Different from other fields of investigation, the role of miRNAs in cardiac tumors still remains difficult to interpret due to the scarcity publications and a lack of narrative focus on this topic. In this article, we summarize the available evidence on miRNAs and cardiac myxomas and propose new pathways for future research. miRNAs play a part in modifying the expression of cardiac transcription factors (miR-335-5p), increasing cell cycle trigger factors (miR-126-3p), interfering with ceramide synthesis (miR-320a), inducing apoptosis (miR-634 and miR-122), suppressing production of interleukins (miR-217), and reducing cell proliferation (miR-218). As such, they have complex and interconnected roles. At present, the study of the complete mechanistic control of miRNA remains a crucial issue, as proper understanding of signaling pathways is essential for the forecasting of therapeutic implications. Other types of cardiac tumors still lack adequate investigation with regard to miRNA. Further research should aim at investigating the causal relationship between different miRNAs and cell overgrowth, considering both myxoma and other histological types of cardiac tumors. We hope that this review will help in understanding this fascinating molecular approach.
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Affiliation(s)
- Antonio Nenna
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (A.N.); (F.L.); (O.G.); (M.C.)
| | - Francesco Loreni
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (A.N.); (F.L.); (O.G.); (M.C.)
| | - Omar Giacinto
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (A.N.); (F.L.); (O.G.); (M.C.)
| | - Camilla Chello
- Integrated Biomedical Science and Bioethics, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Pierluigi Nappi
- Cardiology, Università degli Studi di Messina, 98122 Messina, Italy;
| | - Massimo Chello
- Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (A.N.); (F.L.); (O.G.); (M.C.)
| | - Francesco Nappi
- Cardiac Surgery, Centre Cardiologique du Nord de Saint Denis, 93200 Paris, France
- Correspondence: ; Tel.: +33-149334104; Fax: +33-149334119
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Santovito D, Weber C. Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease. Nat Rev Cardiol 2022; 19:620-638. [PMID: 35304600 DOI: 10.1038/s41569-022-00680-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/14/2022] [Indexed: 02/08/2023]
Abstract
Research showing that microRNAs (miRNAs) are versatile regulators of gene expression has instigated tremendous interest in cardiovascular research. The overwhelming majority of studies are predicated on the dogmatic notion that miRNAs regulate the expression of specific target mRNAs by inhibiting mRNA translation or promoting mRNA decay in the RNA-induced silencing complex (RISC). These efforts mostly identified and dissected contributions of multiple regulatory networks of miRNA-target mRNAs to cardiovascular pathogenesis. However, evidence from studies in the past decade indicates that miRNAs also operate beyond this canonical paradigm, featuring non-conventional regulatory functions and cellular localizations that have a pathophysiological role in cardiovascular disease. In this Review, we highlight the functional relevance of atypical miRNA biogenesis and localization as well as RISC heterogeneity. Moreover, we delineate remarkable non-canonical examples of miRNA functionality, including direct interactions with proteins beyond the Argonaute family and their role in transcriptional regulation in the nucleus and in mitochondria. We scrutinize the relevance of non-conventional biogenesis and non-canonical functions of miRNAs in cardiovascular homeostasis and pathology, and contextualize how uncovering these non-conventional properties can expand the scope of translational research in the cardiovascular field and beyond.
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Affiliation(s)
- Donato Santovito
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), Munich, Germany. .,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. .,Institute for Genetic and Biomedical Research (IRGB), Unit of Milan, National Research Council, Milan, Italy.
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), Munich, Germany. .,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. .,Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. .,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
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