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      LncRNA H19 ameliorates myocardial infarction‐induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A

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          Abstract

          Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide, and novel therapeutic targets still need to be investigated to alleviate myocardial injury and the ensuing maladaptive cardiac remodelling. Accumulating studies have indicated that lncRNA H19 might exert a crucial regulatory effect on cardiovascular disease. In this study, we aimed to explore the biological function and molecular mechanism of H19 in MI. To investigate the biological functions of H19, miRNA‐22‐3p and KDM3A, gain‐ and loss‐of‐function experiments were performed. In addition, bioinformatics analysis, dual‐luciferase reporter assays, RNA immunoprecipitation (RIP) assays, RNA pull‐down assays, quantitative RT‐PCR and Western blot analyses as well as rescue experiments were conducted to reveal an underlying competitive endogenous RNA (ceRNA) mechanism. We found that H19 was significantly down‐regulated after MI. Functionally, enforced H19 expression dramatically reduced infarct size, improved cardiac performance and alleviated cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation. However, H19 knockdown resulted in the opposite effects. Bioinformatics analysis and dual‐luciferase assays revealed that, mechanistically, miR‐22‐3p was a direct target of H19, which was also confirmed by RIP and RNA pull‐down assays in primary cardiomyocytes. In addition, bioinformatics analysis and dual‐luciferase reporter assays also demonstrated that miRNA‐22‐3p directly targeted the KDM3A gene. Moreover, subsequent rescue experiments further verified that H19 regulated the expression of KDM3A to ameliorate MI‐induced myocardial injury in a miR‐22‐3p‐dependent manner. The present study revealed the critical role of the lncRNAH19/miR‐22‐3p/KDM3A pathway in MI. These findings suggest that H19 may act as a potential biomarker and therapeutic target for MI.

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          Most cited references28

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          The NLRP3 inflammasome in acute myocardial infarction

          The heart is extremely sensitive to ischaemic injury. During an acute myocardial infarction (AMI) event, the injury is initially caused by reduced blood supply to the tissues, which is then further exacerbated by an intense and highly specific inflammatory response that occurs during reperfusion. Numerous studies have highlighted the central role of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in this process. The inflammasome, an integral part of the innate immune system, is a macromolecular protein complex that finely regulates the activation of caspase 1 and the production and secretion of powerful pro-inflammatory cytokines such as IL-1β and IL-18. In this Review, we summarize evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in experimental models, and the data supporting the role of the NLRP3 inflammasome in AMI and its consequences on adverse cardiac remodelling, cytokine-mediated systolic dysfunction, and heart failure.
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            The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489.

            Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years.
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              Management of cardiogenic shock complicating myocardial infarction: an update 2019

              Cardiogenic shock (CS) remains the most common cause of death in patients admitted with acute myocardial infarction (AMI) and mortality remained nearly unchanged in the range of 40–50% during the last two decades. Early revascularization, vasopressors and inotropes, fluids, mechanical circulatory support, and general intensive care measures are widely used for CS management. However, there is only limited evidence for any of the above treatment strategies except for revascularization and the relative ineffectiveness of intra-aortic balloon pumping. This updated review will outline the management of CS complicating AMI with major focus on state-of-the art treatment.
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                Author and article information

                Contributors
                hong-jiang@whu.edu.cn
                364580342@qq.com
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                21 November 2019
                January 2020
                : 24
                : 1 ( doiID: 10.1111/jcmm.v24.1 )
                : 1099-1115
                Affiliations
                [ 1 ] Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
                [ 2 ] Cardiovascular Research Institute Wuhan University Wuhan China
                [ 3 ] Hubei Key Laboratory of Cardiology Wuhan China
                Author notes
                [*] [* ] Correspondence

                Hong Jiang and Jing Chen, Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, Hubei Province, China.

                Emails: hong-jiang@ 123456whu.edu.cn ; 364580342@ 123456qq.com

                Author information
                https://orcid.org/0000-0002-6823-7755
                Article
                JCMM14846
                10.1111/jcmm.14846
                6933349
                31755219
                5df536a2-9686-4780-81ae-7a1039010c2f
                © 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 September 2019
                : 25 October 2019
                : 03 November 2019
                Page count
                Figures: 8, Tables: 1, Pages: 17, Words: 8989
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81200156
                Award ID: 81570331
                Funded by: Nature Science Foundation of Hubei Province
                Award ID: 2018CFB240
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:27.12.2019

                Molecular medicine
                kdm3a,lncrna h19,mir‐22‐3p,myocardial infarction
                Molecular medicine
                kdm3a, lncrna h19, mir‐22‐3p, myocardial infarction

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