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.

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.

• Authors: Alia Ellawindy, Kimio Satoh, Shinichiro Sunamura, Nobuhiro Kikuchi, Kota Suzuki, Tatsuro Minami, Shohei Ikeda, Shinichi Tanaka, Toru Shimizu, Budbazar Enkhjargal, Satoshi Miyata, Yuhto Taguchi, Tetsuya Handoh, Kenta Kobayashi, Kazuto Kobayashi, Keiko Nakayama, Masahito Miura, Hiroaki Shimokawa
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 10 Pg. 2172-84 (Oct 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 26315406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• rho-Associated Kinases

Topics

• Animals
• Arrhythmogenic Right Ventricular Dysplasia (metabolism, mortality, physiopathology)
• Desmosomes (metabolism)
• Disease Models, Animal
• Female
• Heart (embryology)
• Humans
• Male
• Mice
• Mice, Knockout
• Myocytes, Cardiac (metabolism)
• Organogenesis (physiology)
• Pregnancy
• Pregnancy, Animal
• Random Allocation
• Signal Transduction
• Wnt Signaling Pathway
• rho-Associated Kinases (metabolism)