Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance
| Autor: | Ryo Tanaka, Takuro Arimura, Taisuke Ishikawa, Akinori Kimura, Shu Nakao, Cheng-Kun Du, Dong Yun Zhan, Takeharu Hayashi, Masayoshi Kuwahara, Antoine Muchir, Sachio Morimoto, Yoshihisa Yamane, Noboru Machida |
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| Přispěvatelé: | Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Comparative Pathophysiology, The University of Tokyo (UTokyo), National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Manchester [Manchester], Ritsumeikan University |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Myosin Light Chains Physiology Transgene [SDV]Life Sciences [q-bio] Cardiomyopathy Mice Transgenic 030204 cardiovascular system & hematology Conduction disturbance Ventricular Function Left 03 medical and health sciences Myosin-Light-Chain Phosphatase Ventricular Dysfunction Left 0302 clinical medicine Heart Rate Physiology (medical) medicine Animals Humans Genetic Predisposition to Disease Myocytes Cardiac Calcium Signaling Phosphorylation Heart Failure rho-Associated Kinases Ventricular Remodeling Chemistry Arrhythmias Cardiac Editorial Focus medicine.disease Fibrosis Myocardial Contraction Cell biology Up-Regulation Mice Inbred C57BL Disease Models Animal Protein Subunits 030104 developmental biology Phenotype Heart failure Small subunit Calcium sensitivity Myosin-light-chain phosphatase Cardiology and Cardiovascular Medicine Cardiomyopathies Cardiac Myosins |
| Zdroj: | AJP-Heart and Circulatory Physiology AJP-Heart and Circulatory Physiology, 2018, 314 (6), pp.H1192-H1202. ⟨10.1152/ajpheart.00696.2017⟩ |
| ISSN: | 0363-6135 1522-1539 |
| DOI: | 10.1152/ajpheart.00696.2017⟩ |
| Popis: | Mutations in genes encoding components of the sarcomere cause cardiomyopathy, which is often associated with abnormal Ca2+sensitivity of muscle contraction. We have previously shown that a heart-specific myosin light chain phosphatase small subunit (hHS-M21) increases the Ca2+sensitivity of muscle contraction. The aim of the present study was to investigate the function of hHS-M21in vivo and the causative role of abnormal Ca2+sensitivity in cardiomyopathy. We generated transgenic mice with cardiac-specific overexpression of hHS-M21. We confirmed that hHS-M21increased the Ca2+sensitivity of cardiac muscle contraction in vivo, which was not followed by an increased phosphorylation of myosin light chain 2 isoforms. hHS-M21transgenic mice developed severe systolic dysfunction with myocardial fibrosis and degeneration of cardiomyocytes in association with sinus bradycardia and atrioventricular conduction defect. The contractile dysfunction and cardiac fibrosis were improved by treatment with the Rho kinase inhibitor fasudil. Our findings suggested that the overexpression of hHS-M21results in cardiac dysfunction and conduction disturbance via non-myosin light chain 2 phosphorylation-dependent regulation.NEW & NOTEWORTHY The present study is the first to develop mice with transgenic overexpression of a heart-specific myosin light chain phosphatase small subunit (hHS-M21) and to examine the effects of hHS-M21on cardiac function. Elevation of hHS-M21induced heart failure with myocardial fibrosis and degeneration of cardiomyocytes accompanied by supraventricular arrhythmias. |
| Databáze: | OpenAIRE |
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