TY - JOUR
T1 - Rho-kinase inhibition during early cardiac development causes arrhythmogenic right ventricular cardiomyopathy in mice
AU - Ellawindy, Alia
AU - Satoh, Kimio
AU - Sunamura, Shinichiro
AU - Kikuchi, Nobuhiro
AU - Suzuki, Kota
AU - Minami, Tatsuro
AU - Ikeda, Shohei
AU - Tanaka, Shinichi
AU - Shimizu, Toru
AU - Enkhjargal, Budbazar
AU - Miyata, Satoshi
AU - Taguchi, Yuhto
AU - Handoh, Tetsuya
AU - Kobayashi, Kenta
AU - Kobayashi, Kazuto
AU - Nakayama, Keiko
AU - Miura, Masahito
AU - Shimokawa, Hiroaki
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/10/25
Y1 - 2015/10/25
N2 - 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 dominantnegative 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.
AB - 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 dominantnegative 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.
KW - Cytoskeletal filaments
KW - Desmosomes
KW - Myocardial fatty change
KW - PPARγ
KW - Rho-kinase
KW - Wnt signaling pathway
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UR - http://www.scopus.com/inward/citedby.url?scp=84942279611&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.115.305872
DO - 10.1161/ATVBAHA.115.305872
M3 - Article
C2 - 26315406
AN - SCOPUS:84942279611
VL - 35
SP - 2172
EP - 2184
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 10
ER -