Alia Ellawindy1, Kimio Satoh1, Shinichiro Sunamura1, Nobuhiro Kikuchi1, Kota Suzuki1, Tatsuro Minami1, Shohei Ikeda1, Shinichi Tanaka1, Toru Shimizu1, Budbazar Enkhjargal1, Satoshi Miyata1, Yuhto Taguchi1, Tetsuya Handoh1, Kenta Kobayashi1, Kazuto Kobayashi1, Keiko Nakayama1, Masahito Miura1, Hiroaki Shimokawa2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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-kinasemice 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: Karyn M Austin; Michael A Trembley; Stephanie F Chandler; Stephen P Sanders; Jeffrey E Saffitz; Dominic J Abrams; William T Pu Journal: Nat Rev Cardiol Date: 2019-09 Impact factor: 32.419
Authors: Tatjana Dorn; Jessica Kornherr; Elvira I Parrotta; Dorota Zawada; Harold Ayetey; Gianluca Santamaria; Laura Iop; Elisa Mastantuono; Daniel Sinnecker; Alexander Goedel; Ralf J Dirschinger; Ilaria My; Svenja Laue; Tarik Bozoglu; Christian Baarlink; Tilman Ziegler; Elisabeth Graf; Rabea Hinkel; Giovanni Cuda; Stefan Kääb; Andrew A Grace; Robert Grosse; Christian Kupatt; Thomas Meitinger; Austin G Smith; Karl-Ludwig Laugwitz; Alessandra Moretti Journal: EMBO J Date: 2018-05-15 Impact factor: 11.598
Authors: Jennifer Lising Roxas; Ross Calvin Monasky; Bryan Angelo P Roxas; Al B Agellon; Asad Mansoor; James B Kaper; Gayatri Vedantam; V K Viswanathan Journal: Cell Mol Gastroenterol Hepatol Date: 2018-04-27