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Gyöngyösi M, Guthrie J, Hasimbegovic E, Han E, Riesenhuber M, Hamzaraj K, Bergler-Klein J, Traxler D, Emmert MY, Hackl M, Derdak S, Lukovic D. Critical analysis of descriptive microRNA data in the translational research on cardioprotection and cardiac repair: lost in the complexity of bioinformatics. Basic Res Cardiol 2025:10.1007/s00395-025-01104-1. [PMID: 40205177 DOI: 10.1007/s00395-025-01104-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/11/2025]
Abstract
The unsuccessful translation of cardiac regeneration and cardioprotection from animal experiments to clinical applications in humans has raised the question of whether microRNA bioinformatics can narrow the gap between animal and human research outputs. We reviewed the literature for the period between 2000 and 2024 and found 178 microRNAs involved in cardioprotection and cardiac regeneration. On analyzing the orthologs and annotations, as well as downstream regulation, we observed species-specific differences in the diverse regulation of the microRNAs and related genes and transcriptomes, the influence of the experimental setting on the microRNA-guided biological responses, and database-specific bioinformatics results. We concluded that, in addition to reducing the number of in vivo experiments, following the 3R animal experiment rules, the bioinformatics approach allows the prediction of several currently unknown interactions between pathways, coding and non-coding genes, proteins, and downstream regulatory elements. However, a comprehensive analysis of the miRNA-mRNA-protein networks needs a profound bioinformatics and mathematical education and training to appropriately design an experimental study, select the right bioinformatics tool with programming language skills and understand and display the bioinformatics output of the results to translate the research data into clinical practice. In addition, using in-silico approaches, a risk of deviating from the in vivo processes exists, with adverse consequences on the translational research.
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Affiliation(s)
- Mariann Gyöngyösi
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
| | - Julia Guthrie
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Zimmermannplatz 10, 1090, Vienna, Austria
| | - Ena Hasimbegovic
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Emilie Han
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Martin Riesenhuber
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Kevin Hamzaraj
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Jutta Bergler-Klein
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Denise Traxler
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Maximilian Y Emmert
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charite (DHZC), Berlin, Germany
| | | | - Sophia Derdak
- Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Dominika Lukovic
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
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2
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Mansour RM, Abdel Mageed SS, Abulsoud AI, Sayed GA, Lutfy RH, Awad FA, Sadek MM, Shaker AAS, Mohammed OA, Abdel-Reheim MA, Elimam H, Doghish AS. From fatty liver to fibrosis: the impact of miRNAs on NAFLD and NASH. Funct Integr Genomics 2025; 25:30. [PMID: 39888504 DOI: 10.1007/s10142-025-01544-x] [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: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease with various levels varying from fatty liver steatosis to acute steatosis which is non-alcoholic steatohepatitis (NASH), which can develop into hepatic failure, as well as in some conditions it can develop into hepatocellular carcinoma (HCC). In the NAFLD and NASH context, aberrant microRNA (miRNA) expression has a thorough contribution to the incidence and development of these liver disorders by influencing key biological actions, involving lipid metabolism, inflammation, and fibrosis. Dysregulated miRNAs can disrupt the balance between lipid accumulation and clearance, exacerbate inflammatory responses, and promote fibrogenesis, thus advancing the severeness of the disorder from simple steatosis to more complex NASH. In the current review, the latest development concerned with the activity of complex regulatory networks of miRNA in the incidence as well as the evolution of NAFLD is to be discussed, also conferring about the miRNAs' role in the onset, pathogenesis as well as diagnosis of NAFLD and NASH discussing miRNAs' role as diagnostic biomarkers and their therapeutic effects on NAFLD/NASH.
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Affiliation(s)
- Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Ghadir A Sayed
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Radwa H Lutfy
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Farah A Awad
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Mohamed M Sadek
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abanoub A S Shaker
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Ge T, Ning B, Wu Y, Chen X, Qi H, Wang H, Zhao M. MicroRNA-specific therapeutic targets and biomarkers of apoptosis following myocardial ischemia-reperfusion injury. Mol Cell Biochem 2024; 479:2499-2521. [PMID: 37878166 DOI: 10.1007/s11010-023-04876-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/05/2023] [Indexed: 10/26/2023]
Abstract
MicroRNAs are single-stranded non-coding RNAs that participate in post-transcriptional regulation of gene expression, it is involved in the regulation of apoptosis after myocardial ischemia-reperfusion injury. For example, the alteration of mitochondrial structure is facilitated by MicroRNA-1 through the regulation of apoptosis-related proteins, such as Bax and Bcl-2, thereby mitigating cardiomyocyte apoptosis. MicroRNA-21 not only modulates the expression of NF-κB to suppress inflammatory signals but also activates the PI3K/AKT pathway to mitigate ischemia-reperfusion injury. Overexpression of MicroRNA-133 attenuates reactive oxygen species (ROS) production and suppressed the oxidative stress response, thereby mitigating cellular apoptosis. MicroRNA-139 modulates the extrinsic death signal of Fas, while MicroRNA-145 regulates endoplasmic reticulum calcium overload, both of which exert regulatory effects on cardiomyocyte apoptosis. Therefore, the article categorizes the molecular mechanisms based on the three classical pathways and multiple signaling pathways of apoptosis. It summarizes the targets and pathways of MicroRNA therapy for ischemia-reperfusion injury and analyzes future research directions.
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Affiliation(s)
- Teng Ge
- School of Graduate, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Bo Ning
- School of Graduate, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Yongqing Wu
- School of Graduate, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Xiaolin Chen
- School of Pharmacy, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Hongfei Qi
- Shaanxi Key Laboratory of Integrated Traditional and Western Medicine for Prevention and Treatment of Cardiovascular Diseases, Institute of Integrative Medicine, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Haifang Wang
- Shaanxi Key Laboratory of Integrated Traditional and Western Medicine for Prevention and Treatment of Cardiovascular Diseases, Institute of Integrative Medicine, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Shiji Avenue, Xianyang, 712046, China
| | - Mingjun Zhao
- Department of Cardiology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Deputy 2, Weiyang West Road, Weicheng District, Xianyang, 712000, China.
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Si C, Gao J, Ma X. Natural killer cell-derived exosome-based cancer therapy: from biological roles to clinical significance and implications. Mol Cancer 2024; 23:134. [PMID: 38951879 PMCID: PMC11218398 DOI: 10.1186/s12943-024-02045-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 06/15/2024] [Indexed: 07/03/2024] Open
Abstract
Natural killer (NK) cells are important immune cells in the organism and are the third major type of lymphocytes besides T cells and B cells, which play an important function in cancer therapy. In addition to retaining the tumor cell killing function of natural killer cells, natural killer cell-derived exosomes cells also have the characteristics of high safety, wide source, easy to preserve and transport. At the same time, natural killer cell-derived exosomes are easy to modify, and the engineered exosomes can be used in combination with a variety of current cancer therapies, which not only enhances the therapeutic efficacy, but also significantly reduces the side effects. Therefore, this review summarizes the source, isolation and modification strategies of natural killer cell-derived exosomes and the combined application of natural killer cell-derived engineered exosomes with other antitumor therapies, which is expected to accelerate the clinical translation process of natural killer cell-derived engineered exosomes in cancer therapy.
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Affiliation(s)
- Chaohua Si
- National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100000, China
| | - Jianen Gao
- National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100000, China.
| | - Xu Ma
- National Research Institute for Family Planning, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100000, China.
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Almaghrbi H, Giordo R, Pintus G, Zayed H. Non-coding RNAs as biomarkers of myocardial infarction. Clin Chim Acta 2023; 540:117222. [PMID: 36627010 DOI: 10.1016/j.cca.2023.117222] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/04/2023] [Accepted: 01/04/2023] [Indexed: 01/08/2023]
Abstract
Non-coding RNAs (ncRNAs) encompass a family of ubiquitous RNA molecules that lack protein-coding potential and have tissue-specific expression. A significant body of evidence indicates that ncRNA's aberrant expression plays a critical role in disease onset and development. NcRNAs' biochemical characteristics such as disease-associated concentration changes, structural stability, and high abundance in body fluids make them promising prognostic and diagnostic biomarkers. Myocardial infarction (MI) is a leading cause of mortality worldwide. Acute myocardial infarction (AMI), the term in use to describe MI's early phase, is generally diagnosed by physical examination, electrocardiogram (ECG), and the presence of specific biomarkers. In this regard, compared to standard MI biomarkers, such as the cardiac troponin isoforms (cTnT & cTnI) and the Creatinine Kinase (CK), ncRNAs appears to provide better sensitivity and specificity, ensuring a rapid and correct diagnosis, an earlier treatment, and consequently a good prognosis for the patients. This review aims to summarize and discuss the most promising and recent data on the potential clinical use of circulating ncRNAs as MI biomarkers. Specifically, we focused primarily on miRNAs and lncRNAs, highlighting their significant specificity and sensitivity, discussing their limitations, and suggesting possible overcoming approaches.
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Affiliation(s)
- Heba Almaghrbi
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Roberta Giordo
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, 505055 Dubai, United Arab Emirates
| | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, 07100 Sassari, Italy; Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research, University of Sharjah, University City Rd, Sharjah 27272, United Arab Emirates.
| | - Hatem Zayed
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
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Banjac N, Vasović V, Stilinović N, Tomas A, Vasović L, Martić N, Prodanović D, Jakovljević V. The Effects of Different Doses of Sildenafil on Coronary Blood Flow and Oxidative Stress in Isolated Rat Hearts. Pharmaceuticals (Basel) 2023; 16:118. [PMID: 36678615 PMCID: PMC9864553 DOI: 10.3390/ph16010118] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 01/15/2023] Open
Abstract
The dose-response relationship of sildenafil effects on cardiac function is not completely elucidated. The aim of this study was to assess the effects of different doses of sildenafil on coronary flow and oxidative stress in isolated rat hearts. Coronary flow and markers of oxidative stress, including nitrite outflow, and superoxide anion production in coronary effluent, were determined for isolated rat hearts. The experiments were performed during control conditions and in the presence of sildenafil (10, 20, 50, 200 nM) alone or with Nω-nitro-L-arginine monomethyl ester (L-NAME) (30 μM). Sildenafil was shown to result in a significant increase in coronary flow at lower coronary perfusion pressure (CPP) values at all administered doses, whereas, with an increase in CPP, a reduction in coronary flow was observed. An increase in nitric oxide (NO) was most pronounced in the group treated with the lowest dose of sildenafil at the highest CPP value. After the inhibition of the NO-cyclic guanosine monophosphate (cGMP) signaling (NOS) system by L-NAME, only a dose of 200 nM sildenafil was high enough to overcome the inhibition and to boost release of O2-. That effect was CPP-dependent, with statistical significance reached at 80, 100 and 120 mmHg. Our findings indicate that sildenafil causes changes in heart vasculature in a dose-dependent manner, with a shift from a vasodilatation effect to vasoconstriction with a pressure increase. The highest dose administered is capable of producing superoxide anion radicals in terms of NOS system inhibition.
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Affiliation(s)
- Nada Banjac
- Medical Faculty, University of Banja Luka, 78000 Republika Srpska, Bosnia and Herzegovina;
| | - Velibor Vasović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (V.V.); (N.S.); (A.T.); (N.M.)
| | - Nebojša Stilinović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (V.V.); (N.S.); (A.T.); (N.M.)
| | - Ana Tomas
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (V.V.); (N.S.); (A.T.); (N.M.)
| | - Lucija Vasović
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
| | - Nikola Martić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (V.V.); (N.S.); (A.T.); (N.M.)
| | - Dušan Prodanović
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (V.V.); (N.S.); (A.T.); (N.M.)
| | - Vladimir Jakovljević
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia;
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miR-1322 protects against the myocardial ischemia via LRP8/PI3K/AKT pathway. Biochem Biophys Res Commun 2023; 638:120-126. [PMID: 36446154 DOI: 10.1016/j.bbrc.2022.10.101] [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: 08/25/2022] [Revised: 09/12/2022] [Accepted: 10/29/2022] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Myocardial infarction is a fatal disease that causes millions of deaths worldwide every year. The damage and recovery of cardiomyocytes are closely related to changes in gene expression. miRNA may be a new therapeutic target of myocardial ischemia-reperfusion. METHODS The differential expression genes were analyzed based on GSE83500, GSE60993 and GSE154733. miRNA expression profile data and clinical data were downloaded from GSE76591. Bioinformatics analysis including limma package, cluster analysis, WGCNA analysis were performed. H9c2 cell hypoxia model and mouse myocardial ischemia model were established. Q-PCR, Western blot and luciferase assay were carried out. RESULTS miR-1322 was identified as a significantly differentially expressed miRNA in myocardial ischemi. Yin Yang 1(YY1) was significantly highly expressed in cells with hypoxia treatment (P < 0.05), and myocardial ischemia mice (P < 0.01), which was identified as the transcription factor of miR-1322. The protein expression of LRP8 was lower in cells with hypoxia treatment and myocardial ischemia mice (P < 0.05) and LRP8 was the target gene of miR-1322. The overexpression of LRP8 could significantly increase the expression of p-PI3K, p-AKT, and P70 S6K (P < 0.05). LRP8 regulated PI3K/AKT/P70 S6K signaling pathway, eventually resulting in cell apoptosis. CONCLUSION Our results suggested that miR-1322 can protect against the myocardial ischemia via LRP8/PI3K/AKT pathway.
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Izzo C, Visco V, Gambardella J, Ferruzzi GJ, Rispoli A, Rusciano MR, Toni AL, Virtuoso N, Carrizzo A, Di Pietro P, Iaccarino G, Vecchione C, Ciccarelli M. Cardiovascular Implications of microRNAs in Coronavirus Disease 2019. J Pharmacol Exp Ther 2023; 384:102-108. [PMID: 35779946 DOI: 10.1124/jpet.122.001210] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/11/2022] [Accepted: 06/15/2022] [Indexed: 01/13/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in coronavirus disease 2019 (COVID-19), and no strategies are available to prevent or specifically address CV events in COVID-19 patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors, and new therapeutic targets. The current report will focus on the role of microRNAs (miRNAs) in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. SIGNIFICANCE STATEMENT: It is essential to identify the molecular mediators of coronavirus disease 2019 (COVID-19) cardiovascular (CV) complications. This report focused on the role of microRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.
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Affiliation(s)
- Carmine Izzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Valeria Visco
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Jessica Gambardella
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Germano Junior Ferruzzi
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Antonella Rispoli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Maria Rosaria Rusciano
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Anna Laura Toni
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Nicola Virtuoso
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Paola Di Pietro
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Guido Iaccarino
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
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9
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Sarohi V, Chakraborty S, Basak T. Exploring the cardiac ECM during fibrosis: A new era with next-gen proteomics. Front Mol Biosci 2022; 9:1030226. [PMID: 36483540 PMCID: PMC9722982 DOI: 10.3389/fmolb.2022.1030226] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/31/2022] [Indexed: 10/24/2023] Open
Abstract
Extracellular matrix (ECM) plays a critical role in maintaining elasticity in cardiac tissues. Elasticity is required in the heart for properly pumping blood to the whole body. Dysregulated ECM remodeling causes fibrosis in the cardiac tissues. Cardiac fibrosis leads to stiffness in the heart tissues, resulting in heart failure. During cardiac fibrosis, ECM proteins get excessively deposited in the cardiac tissues. In the ECM, cardiac fibroblast proliferates into myofibroblast upon various kinds of stimulations. Fibroblast activation (myofibroblast) contributes majorly toward cardiac fibrosis. Other than cardiac fibroblasts, cardiomyocytes, epithelial/endothelial cells, and immune system cells can also contribute to cardiac fibrosis. Alteration in the expression of the ECM core and ECM-modifier proteins causes different types of cardiac fibrosis. These different components of ECM culminated into different pathways inducing transdifferentiation of cardiac fibroblast into myofibroblast. In this review, we summarize the role of different ECM components during cardiac fibrosis progression leading to heart failure. Furthermore, we highlight the importance of applying mass-spectrometry-based proteomics to understand the key changes occurring in the ECM during fibrotic progression. Next-gen proteomics studies will broaden the potential to identify key targets to combat cardiac fibrosis in order to achieve precise medicine-development in the future.
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Affiliation(s)
- Vivek Sarohi
- School of Biosciences and Bioengineering, Indian Institute of Technology (IIT)- Mandi, Himachal Pradesh, India
- BioX Center, Indian Institute of Technology (IIT)- Mandi, Himachal Pradesh, India
| | - Sanchari Chakraborty
- School of Biosciences and Bioengineering, Indian Institute of Technology (IIT)- Mandi, Himachal Pradesh, India
- BioX Center, Indian Institute of Technology (IIT)- Mandi, Himachal Pradesh, India
| | - Trayambak Basak
- School of Biosciences and Bioengineering, Indian Institute of Technology (IIT)- Mandi, Himachal Pradesh, India
- BioX Center, Indian Institute of Technology (IIT)- Mandi, Himachal Pradesh, India
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10
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Cardiovascular Disease-Associated MicroRNAs as Novel Biomarkers of First-Trimester Screening for Gestational Diabetes Mellitus in the Absence of Other Pregnancy-Related Complications. Int J Mol Sci 2022; 23:ijms231810635. [PMID: 36142536 PMCID: PMC9501303 DOI: 10.3390/ijms231810635] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM.
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11
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MicroRNA Let-7a, -7e and -133a Attenuate Hypoxia-Induced Atrial Fibrosis via Targeting Collagen Expression and the JNK Pathway in HL1 Cardiomyocytes. Int J Mol Sci 2022; 23:ijms23179636. [PMID: 36077031 PMCID: PMC9455749 DOI: 10.3390/ijms23179636] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/29/2022] Open
Abstract
Fibrosis is a hallmark of atrial structural remodeling. The main aim of this study was to investigate the role of micro-ribonucleic acids (miRNAs) in the modulation of fibrotic molecular mechanisms in response to hypoxic conditions, which may mediate atrial fibrosis. Under a condition of hypoxia induced by a hypoxia chamber, miRNA arrays were used to identify the specific miRNAs associated with the modulation of fibrotic genes. Luciferase assay, real-time polymerase chain reaction, immunofluorescence and Western blotting were used to investigate the effects of miRNAs on the expressions of the fibrotic markers collagen I and III (COL1A, COL3A) and phosphorylation levels of the stress kinase c-Jun N-terminal kinase (JNK) pathway in a cultured HL-1 atrial cardiomyocytes cell line. COL1A and COL3A were found to be the direct regulatory targets of miR-let-7a, miR-let-7e and miR-133a in hypoxic atrial cardiac cells in vitro. The expressions of COL1A and COL3A were influenced by treatment with miRNA mimic and antagomir while hypoxia-induced collagen expression was inhibited by the delivery of miR-133a, miR-let-7a or miR-let-7e. The JNK pathway was critical in the pathogenesis of atrial fibrosis. The JNK inhibitor SP600125 increased miRNA expressions and repressed the fibrotic markers COL1A and COL3A. In conclusion, MiRNA let-7a, miR-let-7e and miR-133a play important roles in hypoxia-related atrial fibrosis by inhibiting collagen expression and post-transcriptional repression by the JNK pathway. These novel findings may lead to the development of new therapeutic strategies.
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12
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Pozniak T, Shcharbin D, Bryszewska M. Circulating microRNAs in Medicine. Int J Mol Sci 2022; 23:ijms23073996. [PMID: 35409354 PMCID: PMC8999557 DOI: 10.3390/ijms23073996] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
Circulating microRNAs (c-microRNAs, c-miRNAs), which are present in almost all biological fluids, are promising sensitive biomarkers for various diseases (oncological and cardiovascular diseases, neurodegenerative pathologies, etc.), and their signatures accurately reflect the state of the body. Studies of the expression of microRNA markers show that they can enable a wide range of diseases to be diagnosed before clinical symptoms are manifested, and they can help to assess a patient’s response to therapy in order to correct and personalize treatments. This review discusses the latest trends in the uses of miRNAs for diagnosing and treating various diseases, viral and non-viral. It is concluded that exogenous microRNAs can be used as high-precision therapeutic agents for these purposes.
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Affiliation(s)
- Tetiana Pozniak
- Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus, 220072 Minsk, Belarus
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 02000 Kyiv, Ukraine
- Correspondence: (T.P.); (D.S.)
| | - Dzmitry Shcharbin
- Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus, 220072 Minsk, Belarus
- Correspondence: (T.P.); (D.S.)
| | - Maria Bryszewska
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
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Zhang Z, Li J, Long C, Han Y, Fan J, Misrani A, Ji X. Regulatory Mechanism of circEIF4G2 Targeting miR-26a in Acute Myocardial Infarction. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:5308372. [PMID: 35340248 PMCID: PMC8942649 DOI: 10.1155/2022/5308372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 02/17/2022] [Indexed: 11/19/2022]
Abstract
Background Acute myocardial infarction (AMI) involves a series of complex cellular and molecular events, including circular RNAs (circRNAs), microRNAs (miRNAs) and other noncoding RNAs. Objective In this study, the regulation mechanism of circEIF4G2 acting on miR-26a on HUVECs (Human Umbilical Vein Endothelial Cells) proliferation, cell cycle and angiogenesis ability was mainly explored in the vascular endothelial growth factor induced (VEGF-induced) angiogenesis model. Methods VEGF induced HUVECs angiogenesis model was constructed, and the expression of circEIF4G2 and miR-26a in VEGF model was detected by qRT-PCR. When circEIF4G2 and miR-26a were knocked down or overexpressed in HUVECs, qRT-PCR was used to detect the expression of circEIF4G2 and miR-26a, CCK-8 was used to detect cell proliferation, flow cytometry was used to detect the cell cycle transition of HUVECs, and cell formation experiment was used to detect the ability of angiogenesis. MiRanda database and Targetscan predicted the binding site of circEIF4G2 and miR-26a, lucifase reporting assay and RNA pull down assay verified the interaction between circEIF4G2 and miR-26a. Results After HUVECs were treated with VEGF, circEIF4G2 was significantly upregulated. After circEIF4G2 was knocked down, the proliferation and angiogenesis of HUVECs cells were decreased, and the process of cell cycle G0/G1 phase was blocked. The overexpression of miR-26a reduced the proliferation and angiogenesis of HUVECs cells and blocked the cell cycle progression of G0/G1 phase. Double lucifase reporter gene assay verified that circEIF4G2 could directly interact with miR-26a through the binding site, and RNA Pull down assay further verified the interaction between circEIF4G2 and miR-26a. When circEIF4G2 and miR-26a were knocked down simultaneously in HUVECs, it was found that knocking down miR-26a could reverse the inhibition of circEIF4G2 on cell proliferation, cycle and angiogenesis. Conclusion In the VEGF model, circEIF4G2 was highly expressed and miR-26a was low expressed. MiR-26a regulates HUVECs proliferation, cycle and angiogenesis by targeting circEIF4G2.
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Affiliation(s)
- Zaiyong Zhang
- Department of Cardiology, Panyu Central Hospital, Guangzhou 511400, China
- Cardiovascular Institute of Panyu District, Guangzhou 511400, China
| | - Jianhao Li
- Department of Cardiology, Panyu Central Hospital, Guangzhou 511400, China
- Cardiovascular Institute of Panyu District, Guangzhou 511400, China
| | - Cheng Long
- South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Panyu Central Hospital, Guangzhou 511400, China
- School of Life Sciences, South China Normal University, Guangzhou 510630, China
| | - Yuanyuan Han
- Department of Radiology, Panyu Central Hospital, Guangzhou 511400, China
| | - Jun Fan
- Department of Cardiology, Panyu Central Hospital, Guangzhou 511400, China
- Cardiovascular Institute of Panyu District, Guangzhou 511400, China
| | - Afzal Misrani
- South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Panyu Central Hospital, Guangzhou 511400, China
| | - Xiangyu Ji
- School of Life Sciences, South China Normal University, Guangzhou 510630, China
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14
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Jayawardena E, Medzikovic L, Ruffenach G, Eghbali M. Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy. Int J Mol Sci 2022; 23:ijms23031512. [PMID: 35163436 PMCID: PMC8836257 DOI: 10.3390/ijms23031512] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/04/2023] Open
Abstract
Coronary artery disease remains the leading cause of death. Acute myocardial infarction (MI) is characterized by decreased blood flow to the coronary arteries, resulting in cardiomyocytes death. The most effective strategy for treating an MI is early and rapid myocardial reperfusion, but restoring blood flow to the ischemic myocardium can induce further damage, known as ischemia-reperfusion (IR) injury. Novel therapeutic strategies are critical to limit myocardial IR injury and improve patient outcomes following reperfusion intervention. miRNAs are small non-coding RNA molecules that have been implicated in attenuating IR injury pathology in pre-clinical rodent models. In this review, we discuss the role of miR-1 and miR-21 in regulating myocardial apoptosis in ischemia-reperfusion injury in the whole heart as well as in different cardiac cell types with special emphasis on cardiomyocytes, fibroblasts, and immune cells. We also examine therapeutic potential of miR-1 and miR-21 in preclinical studies. More research is necessary to understand the cell-specific molecular principles of miRNAs in cardioprotection and application to acute myocardial IR injury.
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15
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Jin L, Zhang Y, Jiang Y, Tan M, Liu C. Circular RNA Rbms1 inhibited the development of myocardial ischemia reperfusion injury by regulating miR-92a/BCL2L11 signaling pathway. Bioengineered 2022; 13:3082-3092. [PMID: 35068339 PMCID: PMC8973616 DOI: 10.1080/21655979.2022.2025696] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Acute myocardial infarction (AMI) is characterized by high morbidity and mortality rates. Circular RNAs collectively participate in the initiation and development of AMI. The purpose of this study was to investigate the role of circRbms1 in AMI. Ischemia-reperfusion (I/R) was performed to establish an AMI model. RT-qPCR and Western blotting were performed to detect mRNA and analyze protein expression, respectively. The interaction between miR-92a and circRbms1/BCL2L11 was confirmed by luciferase and RNA pull-down assays. circRbms1 is overexpressed in AMI. However, circRbms1 knockdown alleviated H9c2 cell apoptosis and reduced the release of reactive oxygen species. circRbms1 targeted miR-92a, the downregulation of which alleviated the effects of circRbms1 knockdown and increased oxidative stress and H9c2 cell apoptosis. Moreover, circRbms1 sponged miR-92a to upregulate BCL2L11, which modulated the expression of apoptosis-related genes. circRbms1 participated in myocardial I/R injury by regulating the miR-92a/BCL2L11 signaling pathway, which may provide a new strategy for the treatment of AMI.
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Affiliation(s)
- Ling Jin
- Department of Clinical Laboratory, Nanjing First Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Yuan Zhang
- Department of Clinical Laboratory, Nanjing First Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Yun Jiang
- Department of Clinical Laboratory, Nanjing First Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Mingjuan Tan
- Department of Clinical Laboratory, Nanjing First Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Caidong Liu
- Department of Clinical Laboratory, Nanjing First Hospital, Affiliated to Nanjing Medical University, Nanjing, China
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16
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Yang W, Zhao L, Xue S, Liu J, Shan J. MiRNA-21 promotes differentiation of bone marrow mesenchymal stem cells into cardiomyocyte-like cells by regulating the Ajuba/Isl1 axis pathway. Arch Med Sci 2022; 18:1672-1677. [PMID: 36457985 PMCID: PMC9710289 DOI: 10.5114/aoms/154956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 09/26/2022] [Indexed: 11/09/2022] Open
Abstract
INTRODUCTION In this study, we aimed to investigate the role of miRNA-21 and the regulating pathway that promotes the differentiation of bone marrow mesenchymal stem cells (BMSCs). METHODS We used miR-21-OE, miR-21-KD, ajuba-OE and ajuba-KD plasmids to infect BMSCs. The expression of miRNA-21, ajuba, Isl1 and cTnI was detected by RT-qPCR, WB and immunofluorescence staining in groups. RESULTS MiRNA-21 over-expression increased the expression of Isl1, and vice versa. Ajuba over-expression decreased the expression of Isl1, and vice versa. Ajuba negatively regulated the differentiation of BMSCs into cardiomyocyte-like cells. CONCLUSIONS MiRNA-21 could regulate differentiation of bone marrow mesenchymal stem cells (BMSCs) to cardiomyocyte-like cells through the ajuba/Isl1 axis pathway.
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Affiliation(s)
- Wengang Yang
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Zhao
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Song Xue
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jidong Liu
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianggui Shan
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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17
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Bautista-Becerril B, Pérez-Dimas G, Sommerhalder-Nava PC, Hanono A, Martínez-Cisneros JA, Zarate-Maldonado B, Muñoz-Soria E, Aquino-Gálvez A, Castillejos-López M, Juárez-Cisneros A, Lopez-Gonzalez JS, Camarena A. miRNAs, from Evolutionary Junk to Possible Prognostic Markers and Therapeutic Targets in COVID-19. Viruses 2021; 14:41. [PMID: 35062245 PMCID: PMC8781105 DOI: 10.3390/v14010041] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 12/21/2021] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic has been a public health issue around the world in the last few years. Currently, there is no specific antiviral treatment to fight the disease. Thus, it is essential to highlight possible prognostic predictors that could identify patients with a high risk of developing complications. Within this framework, miRNA biomolecules play a vital role in the genetic regulation of various genes, principally, those related to the pathophysiology of the disease. Here, we review the interaction of host and viral microRNAs with molecular and cellular elements that could potentiate the main pulmonary, cardiac, renal, circulatory, and neuronal complications in COVID-19 patients. miR-26a, miR-29b, miR-21, miR-372, and miR-2392, among others, have been associated with exacerbation of the inflammatory process, increasing the risk of a cytokine storm. In addition, increased expression of miR-15b, -199a, and -491 are related to the prognosis of the disease, and miR-192 and miR-323a were identified as clinical predictors of mortality in patients admitted to the intensive care unit. Finally, we address miR-29, miR-122, miR-155, and miR-200, among others, as possible therapeutic targets. However, more studies are required to confirm these findings.
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Affiliation(s)
- Brandon Bautista-Becerril
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; (B.B.-B.); (A.J.-C.)
- Escuela Superior de Medicina, Departamento de Posgrado, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.P.-D.); (E.M.-S.)
| | - Guillermo Pérez-Dimas
- Escuela Superior de Medicina, Departamento de Posgrado, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.P.-D.); (E.M.-S.)
| | - Paola C. Sommerhalder-Nava
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Mexico City 52786, Mexico; (P.C.S.-N.); (A.H.); (B.Z.-M.)
| | - Alejandro Hanono
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Mexico City 52786, Mexico; (P.C.S.-N.); (A.H.); (B.Z.-M.)
| | | | - Bárbara Zarate-Maldonado
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Mexico City 52786, Mexico; (P.C.S.-N.); (A.H.); (B.Z.-M.)
| | - Evangelina Muñoz-Soria
- Escuela Superior de Medicina, Departamento de Posgrado, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.P.-D.); (E.M.-S.)
| | - Arnoldo Aquino-Gálvez
- Laboratorio de Biología Molecular, Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Manuel Castillejos-López
- Departamento de Epidemiología Hospitalaria e Infectología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Armida Juárez-Cisneros
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; (B.B.-B.); (A.J.-C.)
| | - Jose S. Lopez-Gonzalez
- Laboratorio de Cáncer Pulmonar, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Angel Camarena
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; (B.B.-B.); (A.J.-C.)
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18
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Majka M, Kleibert M, Wojciechowska M. Impact of the Main Cardiovascular Risk Factors on Plasma Extracellular Vesicles and Their Influence on the Heart's Vulnerability to Ischemia-Reperfusion Injury. Cells 2021; 10:3331. [PMID: 34943838 PMCID: PMC8699798 DOI: 10.3390/cells10123331] [Citation(s) in RCA: 5] [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: 10/31/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
The majority of cardiovascular deaths are associated with acute coronary syndrome, especially ST-elevation myocardial infarction. Therapeutic reperfusion alone can contribute up to 40 percent of total infarct size following coronary artery occlusion, which is called ischemia-reperfusion injury (IRI). Its size depends on many factors, including the main risk factors of cardiovascular mortality, such as age, sex, systolic blood pressure, smoking, and total cholesterol level as well as obesity, diabetes, and physical effort. Extracellular vesicles (EVs) are membrane-coated particles released by every type of cell, which can carry content that affects the functioning of other tissues. Their role is essential in the communication between healthy and dysfunctional cells. In this article, data on the variability of the content of EVs in patients with the most prevalent cardiovascular risk factors is presented, and their influence on IRI is discussed.
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Affiliation(s)
- Miłosz Majka
- Laboratory of Centre for Preclinical Research, Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland; (M.M.); (M.K.)
| | - Marcin Kleibert
- Laboratory of Centre for Preclinical Research, Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland; (M.M.); (M.K.)
| | - Małgorzata Wojciechowska
- Laboratory of Centre for Preclinical Research, Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland; (M.M.); (M.K.)
- Invasive Cardiology Unit, Independent Public Specialist Western Hospital John Paul II, Daleka 11, 05-825 Grodzisk Mazowiecki, Poland
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19
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Chen S, Fang H, Liu R, Fang Y, Wu Z, Xie P. miR-6718-5p and miR-4329 can be used as potential biomarkers for acute myocardial infarction. J Card Surg 2021; 36:3721-3728. [PMID: 34338363 DOI: 10.1111/jocs.15868] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/26/2021] [Accepted: 07/05/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND The prevention and prognosis of the onset or recurrence of acute myocardial infarction (AMI) is a difficult problem in contemporary research. METHODS In this study, peripheral blood samples were collected from seven patients with AMI and nine healthy adults, and exosome microRNAs (miRNAs) were extracted. The miRNA differential expression profiles of serum exosomes in patients with AMI were obtained by using the next-generation sequencing technology combined with bioinformatics analysis. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to verify the primary screening of differential exosome miRNAs to reveal the possible mechanism of their action on AMI. RESULTS Compared with healthy individuals, 544 miRNAs were upregulated and 518 miRNAs were downregulated in AMI patients preoperatively. Among these miRNAs, we selected miR-6718 and miR-4329 for qPCR verification. The expression of miR6718 and miR-4329 in patients with myocardial infarction was significantly lower than that in normal controls.
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Affiliation(s)
- Shaoyuan Chen
- Department of Cardiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China.,Department of Cardiology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518052, China
| | - Hongcheng Fang
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, 518104, China
| | - Rongzhi Liu
- Department of Cardiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China.,Department of Cardiology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518052, China
| | - Yeqing Fang
- Department of Cardiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China.,Department of Cardiology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518052, China
| | - Zhenyuan Wu
- Department of Cardiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China.,Department of Cardiology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518052, China
| | - Peiyi Xie
- Department of Cardiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China.,Department of Cardiology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518052, China
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20
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Lee GK, Hsieh YP, Hsu SW, Lan SJ. Exploring diagnostic and prognostic predictive values of microRNAs for acute myocardial infarction: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e26627. [PMID: 34398018 PMCID: PMC8294880 DOI: 10.1097/md.0000000000026627] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 11/10/2020] [Accepted: 06/07/2021] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE Previous investigations yielded inconsistent results for diagnostic and prognostic predictive values of MicroRNAs (miRNAs) for acute myocardial infarction (AMI). METHODS AND RESULTS We systematically searched on PubMed and Web of Science for articles explored association of miRNAs and AMI published from January 1989 to March 2019. For diagnostic studies, a summary of sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic odds ratio (DOR), which indicated the accuracy of microRNAs in the differentiation of AMI and no AMI, were calculated from the true positive (TP), true negative (TN), false positive (FP), and false negative (FN) of each study. In addition, the summary receive-operating characteristics (SROC) curve was constructed to summarize the TP and FP rates. For follow-up study, we computed hazard ratios (HRs) and 95% confidence intervals (CIs) for individual clinical outcomes. The meta-analysis showed a sensitivity [0.72 (95% CI: 0.61--0.81)] and specificity [0.88 (95% CI: 0.79--0.94)] of miR-1 for AMI. In addition, miR-133 showed a sensitivity [0.73 (95% CI: 0.55--0.85)] and specificity [0.88 (95% CI: 0.74--0.95)] for AMI. Moreover, the present study showed a sensitivity [0.83 (95% CI: 0.74--0.89)] and specificity [0.96 (95% CI: 0.82--0.99)] of miR-208 for AMI. A significant association was found between miR-208 and mortality after AMI (HR 1.09, 95% CI 1.01--1.18). It also indicated a sensitivity [0.84 (95% CI: 0.70--0.92)] and specificity [0.97 (95% CI: 0.87--0.99)] of miR-499 for AMI. CONCLUSIONS Circulating miR-1, miR-133, miR-208, and miR-499 showed diagnostic values in AMI.
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Affiliation(s)
- Gien-Kuo Lee
- Department of Healthcare Administration, Asia University, Taichung, Taiwan
- BenQ medical center, Emergency Department, Nanjing, China
- Wei Gong Memorial Hospital, Emergency Department, Miaoli, Taiwan
| | - Yen-Ping Hsieh
- Department of Long Term Care, National Quemoy University, Taiwan
| | - Shang-Wei Hsu
- Department of Healthcare Administration, Asia University, Taichung, Taiwan
| | - Shou-Jen Lan
- Department of Healthcare Administration, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
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21
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Lin Y, Fu S, Yao Y, Li Y, Zhao Y, Luo L. Heart failure with preserved ejection fraction based on aging and comorbidities. J Transl Med 2021; 19:291. [PMID: 34229717 PMCID: PMC8259336 DOI: 10.1186/s12967-021-02935-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 06/10/2021] [Indexed: 12/25/2022] Open
Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is a leading cause of hospitalizations and mortality when diagnosed at the age of ≥ 65 years. HFpEF represents multifactorial and multisystemic syndrome and has different pathophysiology and phenotypes. Its diagnosis is difficult to be established based on left ventricular ejection fraction and may benefit from individually tailored approaches, underlying age-related changes and frequent comorbidities. Compared with the rapid development in the treatment of heart failure with reduced ejection fraction, HFpEF presents a great challenge and needs to be addressed considering the failure of HF drugs to improve its outcomes. Further extensive studies on the relationships between HFpEF, aging, and comorbidities in carefully phenotyped HFpEF subgroups may help understand the biology, diagnosis, and treatment of HFpEF. The current review summarized the diagnostic and therapeutic development of HFpEF based on the complex relationships between aging, comorbidities, and HFpEF.
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Affiliation(s)
- Ying Lin
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, 572013, China
| | - Shihui Fu
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, 572013, China.
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
| | - Yao Yao
- Centre for the Study of Ageing and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC, 27708, USA
- Centre for Healthy Ageing and Development Studies, National School of Development, Peking University, Beijing, 100871, China
| | - Yulong Li
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Yali Zhao
- Central Laboratory, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, 572013, China.
| | - Leiming Luo
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
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22
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Yang H, Su J, Meng W, Chen X, Xu Y, Sun B. MiR-518a-5p Targets GZMB to Extenuate Vascular Endothelial Cell Injury Induced by Hypoxia-Reoxygenation and Thereby Improves Myocardial Ischemia. Int Heart J 2021; 62:658-665. [PMID: 33994508 DOI: 10.1536/ihj.20-619] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
To probe the function of miR-518a-5p/Granzyme B (GZMB) in hypoxia/reoxygenation (H/R) -induced vascular endothelial cell injury.The key genes of myocardial infarction were screened by bioinformatic methods. The upstream micro RNAs (miRNAs) of GZMB were predicted by TargetScan. The binding of miR-518a-5p to GZMB was verified with luciferase reporter assay. The H/R model was constructed with human vascular endothelial cell (HUVEC) in vitro. Cell Counting Kit-8 (CCK8) assay was performed to detect cell proliferation. Western blot was utilized to evaluate the levels of indicated proteins.GZMB was up-regulated in patients with myocardial infarction and identified as the key gene by the bioinformatics analysis. Then the prediction from TargetScan indicated that miR-518a-5p, which is down-regulated in myocardial infarction patients, might be the potential upstream miRNA for GZMB. The following experiments verified that miR-518a-5p could bind to the 3'UTR of GZMB and negatively modulates GZMB expression. More importantly, the miR-518a-5p mimic enhanced cell proliferation and repressed apoptosis of H/R-injured HUVEC cells by inhibiting GZMB expression.We proved that miR-518a-5p could partly attenuate H/R-induced HUVEC cell injury by targeting GZMB, and perhaps the miR-518a-5p/GZMB axis could be potential therapeutic targets for myocardial infarction.
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Affiliation(s)
- Hui Yang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University
| | - Jingjing Su
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University
| | - Weixin Meng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University
| | - Xiaoya Chen
- Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University
| | - Ying Xu
- Editorial Department, Journal of Harbin Medical University
| | - Bo Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University
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23
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Benomyl induced oxidative stress related DNA damage and apoptosis in H9c2 cardiomyoblast cells. Toxicol In Vitro 2021; 75:105180. [PMID: 33930522 DOI: 10.1016/j.tiv.2021.105180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/21/2021] [Accepted: 04/25/2021] [Indexed: 11/23/2022]
Abstract
Benomyl, benzimidazole group pesticide, has been prohibited in Europe and USA since 2003 due to its toxic effects and it has been still determined as food and environmental contaminant. In the present study, the toxic effect mechanisms of benomyl were evaluated in rat cardiomyoblast (H9c2) cells. Cytotoxicity was determined by MTT and NRU assay and, oxidative stress potential was evaluated by reactive oxygen species (ROS) production and glutathione levels. DNA damage was assessed by alkaline comet assay. Relative expressions of apoptosis related genes were evaluated; furthermore, NF-κB and JNK protein levels were determined. At 4 μM concentration (at which cell viability was >70%), benomyl increased 2-fold of ROS production level and 2-fold of apoptosis as well as DNA damage. Benomyl down-regulated miR21, TNF-α and Akt1 ≥ 48.75 and ≥ 97.90; respectively. PTEN, JNK and NF-κB expressions were upregulated. The dramatic changes in JNK and NF-κB expression levels were not observed in protein levels. These findings showed the oxidative stress related DNA damage and apoptosis in cardiomyoblast cells exposed to benomyl. However, further mechanistic and in vivo studies are needed to understand the cardiotoxic effects of benomyl and benzimidazol fungucides.
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24
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Wintrich J, Kindermann I, Ukena C, Selejan S, Werner C, Maack C, Laufs U, Tschöpe C, Anker SD, Lam CSP, Voors AA, Böhm M. Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future. Clin Res Cardiol 2020; 109:1079-1098. [PMID: 32236720 PMCID: PMC7449942 DOI: 10.1007/s00392-020-01633-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF.
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Affiliation(s)
- Jan Wintrich
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany.
| | - Ingrid Kindermann
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Christian Ukena
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Simina Selejan
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Christian Werner
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Christoph Maack
- Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie im Department für Innere Medizin, Neurologie und Dermatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Carsten Tschöpe
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site, Berlin, Germany
- Berlin-Brandenburg Institute of Health/Center for Regenerative Therapies (BIHCRT), Berlin, Germany
| | - Stefan D Anker
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site, Berlin, Germany
- Berlin-Brandenburg Institute of Health/Center for Regenerative Therapies (BIHCRT), Berlin, Germany
| | - Carolyn S P Lam
- National Heart Centre, Singapore and Duke-National University of Singapore, Singapore, Singapore
- University Medical Centre Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, Australia
| | - Adriaan A Voors
- University Medical Centre Groningen, Groningen, The Netherlands
| | - Michael Böhm
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
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Liu J, Zuo X, Han J, Dai Q, Xu H, Liu Y, Cui S. MiR-9-5p inhibits mitochondrial damage and oxidative stress in AD cell models by targeting GSK-3β. Biosci Biotechnol Biochem 2020; 84:2273-2280. [PMID: 32713252 DOI: 10.1080/09168451.2020.1797469] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
This study aims to investigate the effects and underlying mechanisms of overexpression microRNA-9-5p (miR-9-5p) on the Aβ-induced mouse hippocampal neuron cell line HT22. Different concentrations of Aβ25-35 (10, 20, 40, 80, and 160 μM) treatment were used to establish AD model in HT22 cells. The CCK-8 assay was used to measure the cell viability. The mRNA expression levels of miR-9-5p and glycogen synthase kinase-3β (GSK-3β) were determined by RT-qPCR. HT22 cell apoptosis was analyzed flow cytometry. MiR-9-5p was down-regulated in Aβ25-35-induced HT22 cells. GSK-3β is a functional target for miR-9-5p. MiR-9-5p overexpression inhibited Aβ25-35-induced mitochondrial dysfunction, cell apoptosis, and oxidative stress by regulating GSK-3β expression in HT22 cells. Furthermore, through targeting GSK-3β, overexpression of miR-9-5p partly activated nuclear factor Nrf2/Keap1 signaling, including part increases of Nrf2, HO-1, SOD-1, GCLC expression and slight decrease of Keap1 expression. Our results showed miR-9-5p may play a powerful role in the pathogenesis of AD.
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Affiliation(s)
- Junli Liu
- Department of Geriatrics, Affiliated Hospital of Qinghai University , Xining, China
| | - Xiaoqin Zuo
- Department of Geriatrics, Affiliated Hospital of Qinghai University , Xining, China
| | - Jixiang Han
- Department of Geriatrics, Affiliated Hospital of Qinghai University , Xining, China
| | - Qingxiang Dai
- Department of Geriatrics, Affiliated Hospital of Qinghai University , Xining, China
| | - Huining Xu
- Department of Geriatrics, Affiliated Hospital of Qinghai University , Xining, China
| | - Ying Liu
- Department of Geriatrics, Affiliated Hospital of Qinghai University , Xining, China
| | - Sen Cui
- Department of Hematology, Affiliated Hospital of Qinghai University , Xining, China
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Liu X, Zhang Y, Jiang P, Cai J, Fu Q, Li X, Li Z. Ultrasonic cardiogram and MiRNA-21 analysis of cardiac dysfunction in patients with cardiac arrest following cardiopulmonary resuscitation. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2020; 190:105284. [PMID: 32018074 DOI: 10.1016/j.cmpb.2019.105284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/08/2019] [Accepted: 12/12/2019] [Indexed: 06/10/2023]
Abstract
PURPOSE To explore correlations between the serum level of miRNA-21 expression and cardiac dysfunction severity after cardiopulmonary resuscitation (CPR) using ultrasonic cardiogram. METHODS Thirty-nine patients with cardiopulmonary arrest receiving successful CPR and forty-one healthy participants were recruited in the study. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunochemiluminometric assays was used to examine the serum miRNA-21 level and the concentration of cardiac troponins T and I, respectively. Indices of Electrocardiogram (ECG) and cardiac dysfunction measured by ultrasound of patients in the case group were used to assess cardiac function after CPR. Furthermore, the correlation between the serum level of miRNA-21 expression and severity of cardiac dysfunction was analyzed by Spearman correlation analysis. RESULTS As compared to the control group, the serum level of miRNA-21 expression, as well as cardiac troponin T and I levels in the case group were significantly higher (p = 0.000). The miRNA-21 expression level in the patients at IV grade of cardiac function were substantially higher than patients at III grade (p = 0.015). There was no significant difference in level of cardiac troponins T and I between patients at III grade and patients at IV grade (p > 0.05). Further, Spearman correlation analysis revealed that the level of miRNA-21 expression was negatively correlated with cardiac function index in the ultrasound imaging: E peak, E/A value, LVEF and LVEDD (r = 0.617, 0.535, 0.612, 0.573, P = 0.012, 0.009, 0.008, 0.011), but was positively correlated with the level of cardiac troponins T and I (r = 0.546,0.582, P = 0.006,0.007) and the severity of cardiac dysfunction (r = 0.859, p < 0.05). CONCLUSION The level of miRNA-21 is higher after CPR is closely related to the severity of cardiac dysfunction that is measured by ultrasound, suggesting that it may serve as a potential biomarker.
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Affiliation(s)
- Xing Liu
- Department of Emergency. Shenzhen Longhua District Center Hospital, Shenzhen, Guangdong 518110, PR China
| | - Yongguang Zhang
- Department of Medicine, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510000, PR China
| | - Peng Jiang
- Department of Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China
| | - Jiachen Cai
- Department of Medicine, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510000, PR China
| | - Qiuhong Fu
- Department of Emergency. Shenzhen Longhua District Center Hospital, Shenzhen, Guangdong 518110, PR China
| | - Xiaolei Li
- Department of Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China
| | - Zhou Li
- Department of Medicine, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510000, PR China.
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Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus-One of Several Possible Reasons for an Increased Cardiovascular Risk. Cells 2020; 9:cells9061557. [PMID: 32604801 PMCID: PMC7349356 DOI: 10.3390/cells9061557] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/19/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3-11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.
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28
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Zhai C, Hu H, Tang G, Pan H, Zhang Y, Qian G. MicroRNA-101a protects against the H 2O 2-induced injury on cardiomyocytes via targeting BCL2L11. Am J Transl Res 2020; 12:2760-2768. [PMID: 32655807 PMCID: PMC7344054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 05/25/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE MicroRNAs (miRs) have been confirmed to be involved in the development of cardiovascular diseases, in spite of numerous studies elucidating the effect and mechanism of miRs in the progression of cardiac ischemia reperfusion injury (I/R), the understanding of their roles is still limited. METHODS All rats underwent the same I/R procedure, while sham group experienced the surgical procedure but without the ligation of left anterior descending coronary artery (LAD). RESULTS Here, we found miR-101a which was proved down-regulated significantly in myocardium and cariomyocytes subjected to I/R and H2O2 treatment respectively. In vivo and in vitro studies determined the protective role of miR-101a from I/R and oxidative stress injury. It attenuated the size of ischemia area and the cardiomycyte apoptosis under I/R and H2O2 treatment. Mechanically, BCL2L11 was predicted and then verified to be targeted by miR-101a. Moreover, rescue experiment and RNA pull down further verified the interaction between miR-101a and BCL2L11. CONCLUSIONS Our findings revealed miR-101a may be a therapeutic target for the therapeutic target for ischemic heart diseases and expanded our understanding of the molecular mechanism underling the progression of I/R injury.
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Affiliation(s)
- Changlin Zhai
- Department of Cardiovascular Diseases, The Affiliated Hospital of Jiaxing UniversityJiaxing, People’s Republic of China
- Institute of AtherosclerosisJiaxing, People’s Republic of China
| | - Huilin Hu
- Department of Cardiovascular Diseases, The Affiliated Hospital of Jiaxing UniversityJiaxing, People’s Republic of China
- Institute of AtherosclerosisJiaxing, People’s Republic of China
| | - Guanmin Tang
- Department of Cardiovascular Diseases, The Affiliated Hospital of Jiaxing UniversityJiaxing, People’s Republic of China
- Institute of AtherosclerosisJiaxing, People’s Republic of China
| | - Haihua Pan
- Department of Cardiovascular Diseases, The Affiliated Hospital of Jiaxing UniversityJiaxing, People’s Republic of China
- Institute of AtherosclerosisJiaxing, People’s Republic of China
| | - Yi Zhang
- Department of Cardiovascular Diseases, Xinhua Hospital, Shanghai Jiaotong University, School of MedicineShanghai, People’s Republic of China
| | - Gang Qian
- Department of Cardiovascular Diseases, The Affiliated Hospital of Jiaxing UniversityJiaxing, People’s Republic of China
- Institute of AtherosclerosisJiaxing, People’s Republic of China
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Khan MS, Yamashita K, Sharma V, Ranjan R, Dosdall DJ. RNAs and Gene Expression Predicting Postoperative Atrial Fibrillation in Cardiac Surgery Patients Undergoing Coronary Artery Bypass Grafting. J Clin Med 2020; 9:jcm9041139. [PMID: 32316120 PMCID: PMC7231013 DOI: 10.3390/jcm9041139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/14/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
Postoperative atrial fibrillation (POAF) is linked with increased morbidity, mortality rate and financial liability. About 20–50% of patients experience POAF after coronary artery bypass graft (CABG) surgery. Numerous review articles and meta-analyses have investigated links between patient clinical risk factors, demographic conditions, and pre-, peri- and post-operative biomarkers to forecast POAF incidence in CABG patients. This narrative review, for the first time, summarize the role of micro-RNAs, circular-RNAs and other gene expressions that have shown experimental evidence to accurately predict the POAF incidence in cardiac surgery patients after CABG. We envisage that identifying specific genomic markers for predicting POAF might be a significant step for the prevention and effective management of this type of post-operative complication and may provide critical perspective into arrhythmogenic substrate responsible for POAF.
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Affiliation(s)
- Muhammad Shuja Khan
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
| | - Kennosuke Yamashita
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
- Division of Cardiovascular Medicine, The University of Utah-Health, Salt Lake City, UT 84132, USA
| | - Vikas Sharma
- Division of Cardiothoracic Surgery, The University of Utah-Health, Salt Lake City, UT 84132, USA;
| | - Ravi Ranjan
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
- Division of Cardiovascular Medicine, The University of Utah-Health, Salt Lake City, UT 84132, USA
- Department of Biomedical Engineering, The University of Utah, Salt Lake City, UT 84112, USA
| | - Derek James Dosdall
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, UT 84112, USA; (M.S.K.); (K.Y.); (R.R.)
- Division of Cardiovascular Medicine, The University of Utah-Health, Salt Lake City, UT 84132, USA
- Division of Cardiothoracic Surgery, The University of Utah-Health, Salt Lake City, UT 84132, USA;
- Department of Biomedical Engineering, The University of Utah, Salt Lake City, UT 84112, USA
- Correspondence: ; Tel.: +1-801-587-2036
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Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases. Int J Mol Sci 2020; 21:ijms21072437. [PMID: 32244558 PMCID: PMC7177375 DOI: 10.3390/ijms21072437] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Mothers with a history of gestational diabetes mellitus (GDM) have an increased risk of developing diabetes in the future and a lifelong cardiovascular risk. Postpartal expression profile of cardiovascular/cerebrovascular disease associated microRNAs was assessed 3–11 years after the delivery in whole peripheral blood of young and middle-aged mothers with a prior exposure to GDM with the aim to identify a high-risk group of mothers at risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases who would benefit from implementation of early primary prevention strategies and long-term follow-up. The hypothesis of the assessment of cardiovascular risk in women was based on the knowledge that a series of microRNAs play a role in the pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases. Abnormal expression profile of multiple microRNAs was found in women with a prior exposure to GDM (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, miR-342-3p, miR-499a-5p, and-miR-574-3p). Postpartal combined screening of miR-1-3p, miR-16-5p, miR-17-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p showed the highest accuracy for the identification of mothers with a prior exposure to GDM at a higher risk of later development of cardiovascular/cerebrovascular diseases (AUC 0.900, p < 0.001, sensitivity 77.48%, specificity 93.26%, cut off >0.611270413). It was able to identify 77.48% mothers with an increased cardiovascular risk at 10.0% FPR. Any of changes in epigenome (upregulation of miR-16-5p, miR-17-5p, miR-29a-3p, and miR-195-5p) that were induced by GDM-complicated pregnancy are long-acting and may predispose mothers affected with GDM to later development of diabetes mellitus and cardiovascular/cerebrovascular diseases. In addition, novel epigenetic changes (upregulation of serious of microRNAs) appeared in a proportion of women that were exposed to GDM throughout the postpartal life. Likewise, a previous occurrence of either GH, PE, and/or FGR, as well as a previous occurrence of GDM, is associated with the upregulation of miR-1-3p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-29a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p. On the other hand, upregulation of miR-16-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-103a-3p, miR-195-5p, miR-342-3p, and miR-574-3p represents a unique feature of aberrant expression profile of women with a prior exposure to GDM. Screening of particular microRNAs may stratify a high-risk group of mothers with a history of GDM who might benefit from implementation of early primary prevention strategies.
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Zhu L, Li Q, Li Q, Qi D, Gao C, Yang H. MicroRNA‐2861 and microRNA‐5115 regulates myocardial ischemia–reperfusion injury through the GPR30/mTOR signaling pathway by binding to GPR30. J Cell Physiol 2020; 235:7791-7802. [PMID: 31930508 DOI: 10.1002/jcp.29427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/20/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Lijie Zhu
- Department of Cardiology Henan Provincial People's Hospital (Zhengzhou University People's Hospital) Zhengzhou P.R. China
- Department of Cardiology Fuwai Central China Cardiovascular Hospital Zhengzhou P.R. China
| | - Qingman Li
- Department of Cardiology Henan Provincial People's Hospital (Zhengzhou University People's Hospital) Zhengzhou P.R. China
- Department of Cardiology Fuwai Central China Cardiovascular Hospital Zhengzhou P.R. China
| | - Qingmin Li
- Department of Cardiology Henan Provincial People's Hospital (Zhengzhou University People's Hospital) Zhengzhou P.R. China
- Department of Cardiology Fuwai Central China Cardiovascular Hospital Zhengzhou P.R. China
| | - Datun Qi
- Department of Cardiology Henan Provincial People's Hospital (Zhengzhou University People's Hospital) Zhengzhou P.R. China
- Department of Cardiology Fuwai Central China Cardiovascular Hospital Zhengzhou P.R. China
| | - Chuanyu Gao
- Department of Cardiology Henan Provincial People's Hospital (Zhengzhou University People's Hospital) Zhengzhou P.R. China
- Department of Cardiology Fuwai Central China Cardiovascular Hospital Zhengzhou P.R. China
| | - Honghui Yang
- Department of Cardiology Henan Provincial People's Hospital (Zhengzhou University People's Hospital) Zhengzhou P.R. China
- Department of Cardiology Fuwai Central China Cardiovascular Hospital Zhengzhou P.R. China
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Li T, Yu SS, Zhou CY, Wang K, Wan YC. MicroRNA-206 inhibition and activation of the AMPK/Nampt signalling pathway enhance sevoflurane post-conditioning-induced amelioration of myocardial ischaemia/reperfusion injury. J Drug Target 2019; 28:80-91. [PMID: 31092059 DOI: 10.1080/1061186x.2019.1616744] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Tao Li
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Shan-Shan Yu
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Chang-Yu Zhou
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Ke Wang
- Department of Gynaecology and Obstetrics, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Ying-Chun Wan
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
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Vengatapathy KV, Ramesh R, Rajappa M, Kulkarni S, Hanifa M. Role of serum microRNA-499 as a diagnostic marker in acute myocardial infarction. COR ET VASA 2019. [DOI: 10.1016/j.crvasa.2018.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kan C, Cao J, Hou J, Jing X, Zhu Y, Zhang J, Guo Y, Chen X. Correlation of miR-21 and BNP with pregnancy-induced hypertension complicated with heart failure and the diagnostic value. Exp Ther Med 2019; 17:3129-3135. [PMID: 30936985 PMCID: PMC6434261 DOI: 10.3892/etm.2019.7286] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/29/2019] [Indexed: 02/06/2023] Open
Abstract
Correlation of miR-21 and B-type natriuretic peptide (BNP) with pregnancy-induced hypertension (PIH) complicated with heart failure and the diagnostic value was investigated. Sixty patients with PIH complicated with heart failure admitted to Affiliated Hospital of Chengde Medical University from July 2016 to July 2017 were enrolled as the experimental group, and 35 normal pregnant women as the control group. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method was used to determine the expression level of plasma miR-21 expression level. An automatic biochemical analyzer was used to determine plasma BNP expression level. Spearmans correlation analysis was used for the correlation analysis of miR-21 and BNP. ROC curve was used for evaluating the diagnostic values of miR-21 and BNP for PIH complicated with heart failure. miR-21 and BNP expression levels were higher in patients with PIH complicated with heart failure than those in the normal individuals, and were increased in line with the heart failure grade (P<0.001). The plasma miR-21 expression was positively correlated with BNP in patients with PIH complicated with heart failure (r=0.685, P<0.001). Both miR-21 and BNP had higher diagnostic values for PIH complicated with heart failure, in the diagnosis, the best cut-off value [odds ratio (OR)] of miR-21 was 1.113, with an area under curve (AUC) of 0.889 and a 95% confidence interval (CI) of 82.05-95.76%; the OR of BNP was 123, with an AUC of 0.747 and a 95% CI of 64.95-84.38%. Blood pressure, six-minute walk test (6MWT), left ventricular ejection fraction (LVEF) and left ventricular end diastolic diameter (LVEDD) were independent risk factors for the occurrence of PIH complicated with heart failure (P<0.05). In conclusion, miR-21 and BNP, highly expressed in patients with PIH complicated with heart failure, are expected to become important biomarkers for diagnosing PIH complicated with heart failure and judging the degree of heart failure in the patients, and worthy of clinical popularization and application.
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Affiliation(s)
- Changli Kan
- Department of Obstetrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Junjie Cao
- Department of Geriatrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Jing Hou
- Department of Obstetrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Xiangyang Jing
- Department of Obstetrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Yanju Zhu
- Department of Obstetrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Jinhuan Zhang
- Department of Obstetrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Yanwei Guo
- Department of Obstetrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Xuerong Chen
- Department of Obstetrics, Yanan Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, P.R. China
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Hromadnikova I, Kotlabova K, Dvorakova L, Krofta L, Sirc J. Postnatal Expression Profile of microRNAs Associated with Cardiovascular and Cerebrovascular Diseases in Children at the Age of 3 to 11 Years in Relation to Previous Occurrence of Pregnancy-Related Complications. Int J Mol Sci 2019; 20:ijms20030654. [PMID: 30717412 PMCID: PMC6387366 DOI: 10.3390/ijms20030654] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 01/29/2019] [Accepted: 01/30/2019] [Indexed: 02/07/2023] Open
Abstract
Children descending from pregnancies complicated by gestational hypertension (GH), preeclampsia (PE) or fetal growth restriction (FGR) have a lifelong cardiovascular risk. The aim of the study was to verify if pregnancy complications induce postnatal alterations in gene expression of microRNAs associated with cardiovascular/cerebrovascular diseases. Twenty-nine microRNAs were assessed in peripheral blood, compared between groups, and analyzed in relation to both aspects, the current presence of cardiovascular risk factors and cardiovascular complications and the previous occurrence of pregnancy complications with regard to the clinical signs, dates of delivery, and Doppler ultrasound examination. The expression profile of miR-21-5p differed between controls and children with a history of uncomplicated pregnancies with abnormal clinical findings. Abnormal expression profile of multiple microRNAs was found in children affected with GH (miR-1-3p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, and miR-342-3p), PE (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-103a-3p, miR-133a-3p, miR-342-3p), and FGR (miR-17-5p, miR-126-3p, miR-133a-3p). The index of pulsatility in the ductus venosus showed a strong positive correlation with miR-210-3p gene expression in children exposed to PE and/or FGR. Any of changes in epigenome (up-regulation of miR-1-3p and miR-133a-3p) that were induced by pregnancy complications are long-acting and may predispose children affected with GH, PE, or FGR to later development of cardiovascular/cerebrovascular diseases. Novel epigenetic changes (aberrant expression profile of microRNAs) appeared in a proportion of children that were exposed to GH, PE, or FGR. Screening of particular microRNAs may stratify a highly risky group of children that might benefit from implementation of early primary prevention strategies.
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Affiliation(s)
- Ilona Hromadnikova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Katerina Kotlabova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Lenka Dvorakova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Ladislav Krofta
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
| | - Jan Sirc
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
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MicroRNA-148b-3p is involved in regulating hypoxia/reoxygenation-induced injury of cardiomyocytes in vitro through modulating SIRT7/p53 signaling. Chem Biol Interact 2018; 296:211-219. [DOI: 10.1016/j.cbi.2018.10.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 09/26/2018] [Accepted: 10/08/2018] [Indexed: 12/21/2022]
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Zhu J, Gu H, Lv X, Yuan C, Ni P, Liu F. LINC-PINT Activates the Mitogen-Activated Protein Kinase Pathway to Promote Acute Myocardial Infarction by Regulating miR-208a-3p. Circ J 2018; 82:2783-2792. [PMID: 30249926 DOI: 10.1253/circj.cj-18-0396] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2024]
Abstract
BACKGROUND This study is performed to explore the differential expression of long intergenic non-coding-p53 induced non-coding transcript, miR-208a-3p and JUN in acute myocardial infarction (AMI) and their potential mechanisms. METHODS AND RESULTS Gene Expression Omnibus, R software, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis were used for analyzing the differentially expressed genes (DEGs) and pathways. The differential expressions of LINC-PINT and miR-208a-3p were examined by qRT-PCR. The expressions of JUN and the mitogen-activated protein kinase (MAPK) pathway-related proteins were analyzed by Western blot. The triphenyltetrazolium chloride (TTC) staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining methods were used to measure the myocardial infarction size and tissue apoptosis respectively. The targeted relationships between miR-208a-3p and LINC-PINT or JUN were confirmed using a dual luciferase reporter assay. DEGs were significantly enriched in the MAPK signaling pathway. LINC-PINT could sponge miR-208a-3p, which targeted and regulated JUN. LINC-PINT and JUN were confirmed to be overexpressed in AMI tissues. Silencing LINC-PINT and JUN could exert a protective influence against AMI. The expression of miR-208a-3p was significantly decreased in AMI tissues, and miR-208a-3p reduced myocardial ischemia-reperfusion injury and apoptosis. Downregulation of LINC-PINT facilitated miR-208a-3p expression and suppressed the protein level of JUN, contributing to the inactivation of the MAPK pathway in the AMI tissues and thus generating protective effects. CONCLUSIONS Knockdown of LINC-PINT inactivated the MAPK pathway by releasing miR-208a-3p and suppressing the JUN, protecting the injury during the process of AMI.
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Affiliation(s)
- Jianzhong Zhu
- Department of Cardiology, The Third Affiliated Hospital of Soochow University
- Department of Cardiology, The First People's Hospital of Kunshan
| | - Huimin Gu
- Department of Cardiology, The First People's Hospital of Kunshan
| | - Xiaolei Lv
- Department of Cardiology, The First People's Hospital of Kunshan
| | - Chunying Yuan
- Department of Anesthesiology, Traditional Chinese Medicine of Kunshan
| | - Ping Ni
- Department of Cardiology, The First People's Hospital of Kunshan
| | - Feng Liu
- Department of Cardiology, Suzhou Kowloon Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
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Izzotti A, La Maestra S, Micale RT, Pulliero A, Geretto M, Balansky R, De Flora S. Modulation of genomic and epigenetic end-points by celecoxib. Oncotarget 2018; 9:33656-33681. [PMID: 30263093 PMCID: PMC6154745 DOI: 10.18632/oncotarget.26062] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 08/16/2018] [Indexed: 01/20/2023] Open
Abstract
Celecoxib, a nonsteroidal anti-inflammatory drug that selectively targets cyclooxygenase-2, is a promising cancer chemopreventive agent. However, safety concerns have been raised in clinical trials evaluating its ability to prevent colorectal adenomas. The rationale for the herein reported studies was to analyze genomic and epigenetic end-points aimed at investigating both the chemopreventive properties of celecoxib towards cigarette smoke-associated molecular alterations and its possible adverse effects. We carried out three consecutive studies in mice treated with either smoke and/or celecoxib. Study 1 investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations (expression of 1,135 microRNAs) in lung and blood of Swiss H mice; Study 2 evaluated the formation of DNA adducts in lung, liver, and heart; and Study 3 evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice. Surprisingly, the oral administration of celecoxib to smoke-free mice resulted in the formation of DNA adducts in both lung and heart and in dysregulation of microRNAs in mouse organs and body fluids. On the other hand, celecoxib attenuated smoke-related DNA damage and dysregulation of microRNA expression. In conclusion, celecoxib showed pleiotropic properties and multiple mechanisms by counteracting the molecular damage produced by smoke in a variety of organs and body fluids. However, administration of celecoxib to non-smoking mice resulted in evident molecular alterations, also including DNA and RNA alterations in the heart, which may bear relevance in the pathogenesis of the cardiovascular adverse effects of this drug.
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Affiliation(s)
- Alberto Izzotti
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | | | - Rosanna T Micale
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy
| | | | - Marta Geretto
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy
| | - Roumen Balansky
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.,National Center of Oncology, 1756 Sofia, Bulgaria
| | - Silvio De Flora
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy
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Yamac AH, Huyut MA, Yilmaz E, Celikkale I, Bacaksiz A, Demir Y, Demir AR, Erturk M, Bakhshaliyev N, Ozdemir R, Kilic U. MicroRNA 199a Is Downregulated in Patients After Coronary Artery Bypass Graft Surgery and Is Associated with Increased Levels of Sirtuin 1 (SIRT 1) Protein and Major Adverse Cardiovascular Events at 3-Year Follow-Up. Med Sci Monit 2018; 24:6245-6254. [PMID: 30192743 PMCID: PMC6139112 DOI: 10.12659/msm.912065] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background The cardioprotective protein SIRT1 is elevated in patients with coronary artery disease (CAD) to compensate for the disease-related adverse effects, but less is known about the prognostic role of SIRT 1 regulating microRNAs in patients after coronary artery bypass graft (CABG) surgery. Material/Methods The expression of the SIRT 1-specific microRNAs miR-199a and miR-195 was analyzed using real-time PCR in 68 patients referred for CABG surgery and 34 control patients undergoing heart valve surgery. In CABG patients, major adverse cardiac and cerebrovascular events (MACCEs), including all-cause death, myocardial infarction (MI), re-vascularization, heart failure symptoms ≥NYHA II, re-hospitalization for any cardiovascular reason, and stroke, were analyzed at a median follow-up (FU) of 3.2 years (range: 3.0–3.6). Results The level of miR-199a in patients with CAD was significantly reduced compared to the control group (relative expression: 0.89±0.49 vs. 1.90±0.90, p=0.001), while SIRT 1 protein was markedly enhanced (p<0.001). In patients undergoing CABG who had MACCEs, miR-199a was significantly lower compared to patients with an uneventful FU (0.71±0.25 vs. 0.98±0.53, p=0.007). Heart failure status, death, and total MACCEs rate were inversely correlated with the amount of miR-199a (p=0.039) at 3-year FU. Conclusions Altered expression of miR-199a in myocardial tissue was found to be associated with SIRT 1 upregulation in patients with CAD undergoing CABG and was associated with an increased MACCEs rate at mid-term follow-up.
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Affiliation(s)
- Aylin Hatice Yamac
- Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Mustafa Ahmet Huyut
- Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Emre Yilmaz
- Department of Cardiology, Mehmet Akif Ersoy Heart Hospital, University of Health Sciences, Istanbul, Turkey
| | - Ilke Celikkale
- Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ahmet Bacaksiz
- Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Yusuf Demir
- Department of Cardiology, Mehmet Akif Ersoy Heart Hospital, University of Health Sciences, Istanbul, Turkey
| | - Ali Riza Demir
- Department of Cardiology, Mehmet Akif Ersoy Heart Hospital, University of Health Sciences, Istanbul, Turkey
| | - Mehmet Erturk
- Department of Cardiology, Mehmet Akif Ersoy Heart Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nijad Bakhshaliyev
- Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ramazan Ozdemir
- Department of Cardiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ulkan Kilic
- Department of Medical Biology, Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
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Gan XT, Karmazyn M. Cardioprotection by ginseng: experimental and clinical evidence and underlying mechanisms. Can J Physiol Pharmacol 2018; 96:859-868. [PMID: 29940129 DOI: 10.1139/cjpp-2018-0192] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Protection of the ischemic and reperfused myocardium represents a major therapeutic challenge. Translating results from animal studies to the clinical setting has been disappointing, yet the need for effective intervention, particularly to limit heart damage following infarction or surgical procedures such as coronary artery bypass grafting, is substantial. Among the many compounds touted as cardioprotective agents is ginseng, a medicinal herb belonging to the genus Panax, which has been used as a medicinal agent for thousands of years, particularly in Asian societies. The biological actions of ginseng are very complex and reflect composition of many bioactive components, although many of the biological and therapeutic effects of ginseng have been attributed to the presence of steroid-like saponins termed ginsenosides. Both ginseng and many ginsenosides have been shown to exert cardioprotective properties in experimental models. There is also clinical evidence that traditional Chinese medications containing ginseng exert cardioprotective properties, although such clinical evidence is less robust primarily owing to the paucity of large-scale clinical trials. Here, we discuss the experimental and clinical evidence for ginseng, ginsenosides, and ginseng-containing formulations as cardioprotective agents against ischemic and reperfusion injury. We further discuss potential mechanisms, particularly as these relate to antioxidant properties.
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Affiliation(s)
- Xiaohong Tracey Gan
- University of Western Ontario, London, ON N6G 2X6, Canada.,University of Western Ontario, London, ON N6G 2X6, Canada
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Kaur H, Sarmah D, Saraf J, Vats K, Kalia K, Borah A, Yavagal DR, Dave KR, Ghosh Z, Bhattacharya P. Noncoding RNAs in ischemic stroke: time to translate. Ann N Y Acad Sci 2018; 1421:19-36. [DOI: 10.1111/nyas.13612] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/11/2017] [Accepted: 01/08/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Harpreet Kaur
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Jackson Saraf
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Kanchan Vats
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Kiran Kalia
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory; Department of Life Science and Bioinformatics; Assam University; Silchar Assam India
| | - Dileep R. Yavagal
- Department of Neurology and Neurosurgery; University of Miami Miller School of Medicine; Miami Florida
| | - Kunjan R. Dave
- Department of Neurology and Neurosurgery; University of Miami Miller School of Medicine; Miami Florida
| | - Zhumur Ghosh
- Department of Bioinformatics; Bose Institute; Kolkata India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Ahmedabad, Gandhinagar Gujarat India
- Department of Neurosurgery, Boston Children's Hospital; Harvard Medical School; Boston Massachusetts
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Meng Q, Liu Y, Huo X, Sun H, Wang Y, Bu F. MicroRNA‑221‑3p contributes to cardiomyocyte injury in H2O2‑treated H9c2 cells and a rat model of myocardial ischemia‑reperfusion by targeting p57. Int J Mol Med 2018; 42:589-596. [PMID: 29693157 DOI: 10.3892/ijmm.2018.3628] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 03/23/2018] [Indexed: 11/06/2022] Open
Abstract
Myocardial ischemia‑reperfusion (I/R) injury is a major cause of cardiovascular disease worldwide, and microRNAs have been implicated in the regulation of pathological and physiological processes in myocardial I/R injury. The present study aimed to investigate the role of microRNA (miR)‑221‑3p in myocardial I/R injury. Cell death and lactate dehydrogenase (LDH) activity were increased in hydrogen peroxide (H2O2)‑treated H9c2 cells, as measured by flow cytometry and an LDH detection kit. The expression of miR‑221‑3p was elevated in H2O2‑incubated cells and in remote areas of the rat I/R model, examined using reverse transcription‑quantitative polymerase chain reaction analysis. The overexpression of miR‑221‑3p enhanced the number of propidium iodide (PI)+ cells and the activity of LDH in H2O2‑treated cells. In I/R‑induced rats, the overexpression of miR‑221‑3p promoted the number of myosin+ cells and inhibited the fractional shortening of left ventricular diameter (FSLVD%). The results showed that the expression of p57 at the gene and protein levels was decreased in H9c2 cells incubated with H2O2 and in rats subjected to I/R surgery; the expression of p57 decreased following the overexpression of miR‑221‑3p. Subsequently, the hypothesis that p57 was the direct target of miR‑221‑3p was confirmed by performing a dual‑luciferase reporter assay. Finally, to examine the function of p57 in myocardial impairment, p57 was transfected into H9c2 cells and administered to the rats prior to undergoing H2O2 treatment and I/R surgery, respectively. The results indicated that p57 attenuated the number of PI+ cells and the activity of LDH in H2O2‑treated cells, whereas p57 downregulated the number of myosin+ cells and upregulated FSLVD% in the I/R‑treated rats. Therefore, these findings suggested that miR‑221‑3p exacerbated the H2O2‑induced myocardial damage in H9c2 cells and myocardial I/R injury in the rat model by modulating p57.
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Affiliation(s)
- Qingfeng Meng
- Department of Cardiology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong 266035, P.R. China
| | - Yang Liu
- Cadre Health Care Department, Qingdao Municipal Hospital (Group), Qingdao No. 9 People's Hospital, Qingdao, Shandong 266000, P.R. China
| | - Xiuyue Huo
- Department of Cardiology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong 266035, P.R. China
| | - Hui Sun
- Department of Cardiology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong 266035, P.R. China
| | - Yingcui Wang
- Department of Cardiology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong 266035, P.R. China
| | - Fangfang Bu
- Department of Cardiology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong 266035, P.R. China
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Xue X, Shi X, Dong H, You S, Cao H, Wang K, Wen Y, Shi D, He B, Li Y. Delivery of microRNA-1 inhibitor by dendrimer-based nanovector: An early targeting therapy for myocardial infarction in mice. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2017; 14:619-631. [PMID: 29269324 DOI: 10.1016/j.nano.2017.12.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 11/05/2017] [Accepted: 12/04/2017] [Indexed: 12/21/2022]
Abstract
Myocardial infarction (MI), known to be rapidly progressed and fatal, necessitates a timely and effective intervention particularly within golden 24 h. The crux is to develop a therapeutic agent that can early target the infarct site with integrated therapeutic capacity. Finding the AT1 receptor being most over-expressed at 24 h after MI, we developed a nanovector (AT1-PEG-DGL) anchored with AT1 targeting peptide, and simultaneously armed it with specific microRNA-1 inhibitor (AMO-1) to attenuate cardiomyocyte apoptosis. In vivo imaging after IV administration demonstrated that AT1-PEG-DGL quickly accumulated in the MI heart during the desired early period, significantly outperforming the control group without AT1 targeting. Most importantly, a pronounced in-vivo anti-apoptosis effect was observed upon a single IV injection. Apoptotic cell death in the infarct border zone was significantly decreased and the myocardial infarct size was reduced by 64.1% as compared with that in MI control group, promising for early MI treatment.
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Affiliation(s)
- Xiaomei Xue
- Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xueyin Shi
- Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haiqing Dong
- Institute for Biomedical Engineering &Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shasha You
- Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huimin Cao
- Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kun Wang
- Institute for Biomedical Engineering &Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ya Wen
- Institute for Biomedical Engineering &Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Donglu Shi
- The Materials Science & Engineering Program, Department of Mechanical & Materials Engineering, College of Engineering & Applied Science, University of Cincinnati, Cincinnati, OH, USA
| | - Bin He
- Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Yongyong Li
- Institute for Biomedical Engineering &Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
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Xu J, Tang Y, Bei Y, Ding S, Che L, Yao J, Wang H, Lv D, Xiao J. miR-19b attenuates H2O2-induced apoptosis in rat H9C2 cardiomyocytes via targeting PTEN. Oncotarget 2017; 7:10870-8. [PMID: 26918829 PMCID: PMC4905445 DOI: 10.18632/oncotarget.7678] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 02/15/2016] [Indexed: 12/21/2022] Open
Abstract
Myocardial ischemia-reperfusion (I-R) injury lacks effective treatments. The miR-17-92 cluster plays important roles in regulating proliferation, apoptosis, cell cycle and other pivotal processes. However, their roles in myocardial I-R injury are largely unknown. In this study, we found that miR-19b was the only member of the miR-17-92 cluster that was downregulated in infarct area of heart samples from a murine model of I-R injury. Meanwhile, downregulation of miR-19b was also detected in H2O2-treated H9C2 cells in vitro mimicking oxidative stress occurring during myocardial I-R injury. Using flow cytometry and Western blot analysis, we found that overexpression of miR-19b decreased H2O2-induced apoptosis and improved cell survival, while downregulation of that had inverse effects. Furthermore, PTEN was negatively regulated by miR-19b at the protein level while silencing PTEN could completely block the aggravated impact of miR-19b inhibitor on H2O2-induced apoptosis in H9C2 cardiomyocytes, indicating PTEN as a downstream target of miR-19b controlling H2O2-induced apoptosis. These data indicate that miR-19b overexpression might be a novel therapy for myocardial I-R injury.
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Affiliation(s)
- Jiahong Xu
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu Tang
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yihua Bei
- Regeneration and Ageing Laboratory, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai, China
| | - Shengguang Ding
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of NanTong University, Nantong, China
| | - Lin Che
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianhua Yao
- Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongbao Wang
- Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dongchao Lv
- Regeneration and Ageing Laboratory, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai, China
| | - Junjie Xiao
- Regeneration and Ageing Laboratory, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai, China
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Stokfisz K, Ledakowicz-Polak A, Zagorski M, Zielinska M. Ischaemic preconditioning - Current knowledge and potential future applications after 30 years of experience. Adv Med Sci 2017; 62:307-316. [PMID: 28511069 DOI: 10.1016/j.advms.2016.11.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 10/19/2016] [Accepted: 11/29/2016] [Indexed: 12/16/2022]
Abstract
Ischaemic preconditioning (IPC) phenomenon has been known for thirty years. During that time several studies showed that IPC provided by brief ischaemic and reperfusion episodes prior to longer ischaemia can bestow a protective effect to both preconditioned and also remote organs. IPC affecting remote organs is called remote ischaemic preconditioning. Initially, most IPC studies were focused on enhancing myocardial resistance to subsequent ischaemia and reperfusion injury. However, preconditioning was found to be a universal phenomenon and was observed in various organs and tissues including the heart, liver, brain, retina, kidney, skeletal muscles and intestine. Currently, there are a lot of simultaneous studies are underway aiming at finding out whether IPC can be helpful in protecting these organs. The mechanism of local and remote IPC is complex and not well known. Several triggers, intracellular pathways and effectors, humoral, neural and induced by genetic changes may be considered potential pathways in the protective activity of local and remote IPC. Local and remote IPC mechanism may potentially serve as heart protection during cardiac surgery and may limit the infarct size of the myocardium, can be a strategy for preventing the development of acute kidney injury development and liver damage during transplantation, may protect the brain against ischaemic injury. In addition, the method is safe, non-invasive, cheap and easily applicable. The main purpose of this review article is to present new advances which would help to understand the potential mechanism of IPC. It also discusses both its potential applications and utility in clinical settings.
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Affiliation(s)
- Karolina Stokfisz
- Intensive Cardiac Therapy Clinic, Department of Invasive Cardiology and Electrocardiology, Medical University, Lodz, Poland.
| | - Anna Ledakowicz-Polak
- Intensive Cardiac Therapy Clinic, Department of Invasive Cardiology and Electrocardiology, Medical University, Lodz, Poland
| | - Maciej Zagorski
- Cardiosurgery Clinic, Department of Cardiology and Cardiosurgery, Medical University, Lodz, Poland
| | - Marzenna Zielinska
- Intensive Cardiac Therapy Clinic, Department of Invasive Cardiology and Electrocardiology, Medical University, Lodz, Poland
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Diao H, Liu B, Shi Y, Song C, Guo Z, Liu N, Song X, Lu Y, Lin X, Li Z. MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3. Biosci Biotechnol Biochem 2017; 81:1712-1720. [PMID: 28661226 DOI: 10.1080/09168451.2017.1343118] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Oxidative stress-induced myocardial apoptosis and necrosis are involved in ischemia/reperfusion (I/R) injury. This study was performed to investigate microRNA (miR)-210's role in oxidative stress-related myocardial damage. The expression of miR-210 was upregulated in myocardial tissues of I/R rats, while that of Bcl-2 adenovirus E1B 19kDa-interacting protein 3 (BNIP3) was downregulated. To simulate in vivo oxidative stress, H9c2 cells were treated with H2O2 for 48 h. MiR-210 level was increased upon H2O2 stimulation, peaked at 8 h, and then decreased. An opposite expression pattern of BNIP3 was observed. BNIP3 was demonstrated as a direct target of miR-210 via luciferase reporter assay. H2O2-induced cell apoptosis was attenuated by miR-210 mimics, whereas aggravated by miR-210 inhibitor. MiR-210 knockdown-induced cell apoptosis in presence of H2O2 was attenuated by BNIP3 siRNA. Our work demonstrates that miR-210 plays a protective role in H2O2-induced cardiomyocyte apoptosis at least by regulating the pro-apoptotic BNIP3.
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Affiliation(s)
- Hongying Diao
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Bin Liu
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Yongfeng Shi
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Chunli Song
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Ziyuan Guo
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Ning Liu
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Xianjing Song
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Yang Lu
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Xiaoye Lin
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
| | - Zhuoran Li
- a Department of Cardiology , The Second Hospital of Jilin University , Changchun , People's Republic of China
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Zhang D, Li Y, Liu S, Wang YC, Guo F, Zhai Q, Jiang J, Ying H. microRNA and thyroid hormone signaling in cardiac and skeletal muscle. Cell Biosci 2017; 7:14. [PMID: 28331574 PMCID: PMC5359910 DOI: 10.1186/s13578-017-0141-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/08/2017] [Indexed: 01/18/2023] Open
Abstract
Thyroid hormone (TH) signaling plays critical roles in the differentiation, growth, metabolism, and physiological function of all organs or tissues, including heart and skeletal muscle. Due to the significant progress in our understanding of the molecular mechanisms that underlie TH action, it's widely accepted that TH signaling is regulated at multiple levels. A growing number of discoveries suggest that microRNAs (miRNAs) act as fine-tune regulators of gene expression and adds sophisticated regulatory tiers to signaling pathways. Recently, some pioneering studies in cardiac and skeletal muscle demonstrating the interplay between miRNAs and TH signaling suggest that miRNAs might mediate and/or modulate TH signaling. This review presents recent advances involving the crosstalk between miRNAs and TH signaling and current evidence showing the importance of miRNA in TH signaling with particular emphasis on the study of muscle-specific miRNAs (myomiRs) in cardiac and skeletal muscle. Although the research of the reciprocal regulation of miRNAs and TH signaling is only at the beginning stage, it has already contributed to our current understanding of both TH action and miRNA biology. We also encourage further investigations to address the relative contributions of miRNAs in TH signaling under physiological and pathological conditions and how a group of miRNAs are coordinated to integrate into the complex hierarchical regulatory network of TH.
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Affiliation(s)
- Duo Zhang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Yan Li
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Shengnan Liu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Yu-Cheng Wang
- Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai Xuhui Central Hospital, 966 Middle Huaihai Road, Shanghai, 200031 China
| | - Feifan Guo
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Qiwei Zhai
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Jingjing Jiang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032 China
| | - Hao Ying
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China.,Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Institute for Nutritional Sciences, Room A1912, New Life Science Building, 320 Yueyang Road, Shanghai, 200031 China
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48
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Bian B, Yu XF, Wang GQ, Teng TM. Role of miRNA-1 in regulating connexin 43 in ischemia-reperfusion heart injury: a rat model. Cardiovasc Pathol 2017; 27:37-42. [PMID: 28081514 DOI: 10.1016/j.carpath.2016.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 12/08/2016] [Accepted: 12/30/2016] [Indexed: 11/25/2022] Open
Abstract
MiRNA-1 may participate in regulating ischemia-reperfusion injury (IRI) by affecting the expression and distribution of connexin 43 (Cx43). The aim of this study is to investigate miR-1 expression and its potential role in regulating Cx43 during ischemic postconditioning (IPOST) in a rat model. Fifty-five Wistar male rats were randomly divided into five groups: N, IR, IPOST, agomir-1, and antagomir-1 group. The hearts were perfused with the Langendorff system. The reperfusion arrhythmia (RA) and myocardial infarct size were observed and recorded. The miRNA-1 expression and the Cx43 expression and distribution were assessed by RT-PCR, immunoblotting, and immunohistochemistry. First, the RA score in the IR group was higher than that in the control group, whereas there was no difference between the IPOST and antagomir-1 groups. Second, the myocardial infarct size was larger in the agomir-1 than in the IPOST group; there was no difference between the antagomir-1 and the IPOST group. Third, the miRNA-1 expression increased by 78% in the agomir-1 group but decreased by 32% in the antagomir-1 group compared with the IPOST group. Fourth, compared with the Control group, the Cx43 expression in the IR group decreased, the Cx43 expression decreased in the agomir-1 group compared with the IPOST group. Fifth, the distribution of Cx43 was irregular and disorganized in the IR and agomir-1 groups. In the IPOST and antagomir-1 groups, Cx43 was neatly distributed in the intercalated disk area. Our findings suggest that IPOST can inhibit the up-regulation of miRNA-1 induced by ischemia-reperfusion and that the down-regulation of miRNA-1 can prevent the decrease and redistribution of Cx43, which will protect the heart from IRI.
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Affiliation(s)
- Bo Bian
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Xue-Fang Yu
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China.
| | - Guo-Qin Wang
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Tian-Ming Teng
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
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Abstract
Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Christopher P. Baines
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
- Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
| | - Ronald J. Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
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50
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de Melo BL, Vieira SS, Antônio EL, Dos Santos LFN, Portes LA, Feliciano RS, de Oliveira HA, Silva JA, de Carvalho PDTC, Tucci PJF, Serra AJ. Exercise Training Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Stenosis. Front Physiol 2016; 7:541. [PMID: 27994552 PMCID: PMC5136544 DOI: 10.3389/fphys.2016.00541] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 10/27/2016] [Indexed: 12/04/2022] Open
Abstract
Introduction: Pulmonary arterial stenosis (PAS) is a congenital defect that causes outflow tract obstruction of the right ventricle (RV). Currently, negative issues are reported in the PAS management: not all patients may be eligible to surgeries; there is often the need for another surgery during passage to adulthood; patients with mild stenosis may have later cardiac adverse repercussions. Thus, the search for approaches to counteract the long-term PAS effects showed to be a current target. At the study herein, we evaluated the cardioprotective role of exercise training in rats submitted to PAS for 9 weeks. Methods and Results: Exercise resulted in improved physical fitness and systolic RV function. Exercise also blunted concentric cavity changes, diastolic dysfunction, and fibrosis induced by PAS. Exercise additional benefits were also reported in a pro-survival signal, in which there were increased Akt1 activity and normalized myocardial apoptosis. These findings were accompanied by microRNA-1 downregulation and microRNA-21 upregulation. Moreover, exercise was associated with a higher myocardial abundance of the sarcomeric protein α-MHC and proteins that modulate calcium handling—ryanodine receptor and Serca 2, supporting the potential role of exercise in improving myocardial performance. Conclusion: Our results represent the first demonstration that exercise can attenuate the RV remodeling in an experimental PAS. The cardioprotective effects were associated with positive modulation of RV function, survival signaling pathway, apoptosis, and proteins involved in the regulation of myocardial contractility.
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Affiliation(s)
- Brunno Lemes de Melo
- Cardiac Physiology Laboratory, Federal University of São Paulo São Paulo, Brazil
| | - Stella S Vieira
- Cardiac Physiology Laboratory, Federal University of São Paulo São Paulo, Brazil
| | - Ednei L Antônio
- Cardiac Physiology Laboratory, Federal University of São Paulo São Paulo, Brazil
| | - Luís F N Dos Santos
- Cardiac Physiology Laboratory, Federal University of São Paulo São Paulo, Brazil
| | - Leslie A Portes
- Cardiac Physiology Laboratory, Federal University of São Paulo São Paulo, Brazil
| | | | | | - José A Silva
- Biophotonic Laboratory, Nove de Julho University São Paulo, Brazil
| | | | - Paulo J F Tucci
- Cardiac Physiology Laboratory, Federal University of São Paulo São Paulo, Brazil
| | - Andrey J Serra
- Cardiac Physiology Laboratory, Federal University of São PauloSão Paulo, Brazil; Biophotonic Laboratory, Nove de Julho UniversitySão Paulo, Brazil
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