title: Rho-Kinase Inhibition During Early Cardiac Development Causes Arrhythmogenic Right Ventricular Cardiomyopathy in Mice.
abstract: OBJECTIVE
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty changes of the right ventricle, ventricular arrhythmias, and sudden death. Though ARVC is currently regarded as a disease of the desmosome, desmosomal gene mutations have been identified only in half of ARVC patients, suggesting the involvement of other associated mechanisms. Rho-kinase signaling is involved in the regulation of intracellular transport and organizes cytoskeletal filaments, which supports desmosomal protein complex at the myocardial cell-cell junctions. Here, we explored whether inhibition of Rho-kinase signaling is involved in the pathogenesis of ARVC.
  
  
  RESULTS
  Using 2 novel mouse models with SM22α- or αMHC-restricted overexpression of dominant-negative Rho-kinase, we show that mice with Rho-kinase inhibition in the developing heart (SM22α-restricted) spontaneously develop cardiac dilatation and dysfunction, myocardial fibrofatty changes, and ventricular arrhythmias, resulting in premature sudden death, phenotypes fulfilling the criteria of ARVC in humans. Rho-kinase inhibition in the developing heart results in the development of ARVC phenotypes in dominant-negative Rho-kinase mice through 3 mechanisms: (1) reduction of cardiac cell proliferation and ventricular wall thickness, (2) stimulation of the expression of the proadipogenic noncanonical Wnt ligand, Wnt5b, and the major adipogenic transcription factor, PPARγ (peroxisome proliferator activated receptor-γ), and inhibition of Wnt/β-catenin signaling, and (3) development of desmosomal abnormalities. These mechanisms lead to the development of cardiac dilatation and dysfunction, myocardial fibrofatty changes, and ventricular arrhythmias, ultimately resulting in sudden premature death in this ARVC mouse model.
  
  
  CONCLUSIONS
  This study demonstrates a novel crucial role of Rho-kinase inhibition during cardiac development in the pathogenesis of ARVC in mice.
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Alia
authors: A
authors: Ellawindy
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Kimio
authors: K
authors: Satoh
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Shinichiro
authors: S
authors: Sunamura
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Nobuhiro
authors: N
authors: Kikuchi
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Kota
authors: K
authors: Suzuki
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Tatsuro
authors: T
authors: Minami
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Shohei
authors: S
authors: Ikeda
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Shinichi
authors: S
authors: Tanaka
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Toru
authors: T
authors: Shimizu
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Budbazar
authors: B
authors: Enkhjargal
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Satoshi
authors: S
authors: Miyata
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Yuhto
authors: Y
authors: Taguchi
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Tetsuya
authors: T
authors: Handoh
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Kenta
authors: K
authors: Kobayashi
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Kazuto
authors: K
authors: Kobayashi
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Keiko
authors: K
authors: Nakayama
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.).
authors: Masahito
authors: M
authors: Miura
authors: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (A.E., K.S., S.S., N.K., K.S., T.M., S.I., S.T., T.S., B.E., S.M., H.S.); and Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan (T.M., S.T.); Department of Clinical Physiology, Health Science, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.T., T.H., M.M.); Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (K.K., K.K.); and United Centers for Advanced Research and Translational Medicine, Core Center of Cancer Research, Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N.). shimo@cardio.med.tohoku.ac.jp.
authors: Hiroaki
authors: H
authors: Shimokawa
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D003896:Desmosomes / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000196:embryology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D038081:Organogenesis / Q000502:physiology*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011897:Random Allocation; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D054460:rho-Associated Kinases
keywords: PPARγ; Rho-kinase; Wnt signaling pathway; cytoskeletal filaments; desmosomes; myocardial fatty change