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.

RhoA/Rho-Kinase in the Cardiovascular System

“…238 On the basis of the role of Rho-kinase in disease processes, we found that the target and therapeutic applications for Rho-kinase inhibitors are mainly in the field of cardiovascular diseases. However, our recent study demonstrated a crucial role for Rho-kinase in cardiac development, 13 which may warn against the use of Rho-kinase inhibitors during pregnancy as in the case of inhibitors of the renin-angiotensin system. 239 To date, we demonstrated that several medications, including statins, calcium channel blockers, and eicosapentaenoic acid, have an indirect inhibitory effect on Rho-kinase.…”

“…[224][225][226] We recently demonstrated that Rhokinase inhibition during cardiac development causes ARVC in mice. 13 Rho-kinase regulates a wide range of cellular functions, including actin cytoskeleton assembly, cell contractility, proliferation, and differentiation, as well as gene expression. 44,227 In addition, the RhoA/Rho-kinase pathway plays an important role in the regulation of adipogenesis.…”

“…[9][10][11][12] In addition, we recently demonstrated the Rho-kinase inhibition in the developing heart results in the development of arrhythmogenic right ventricular cardiomyopathy (ARVC). 13 Herein, we will review the recent advances on the importance and regulation of Rho-kinase in the cardiovascular system.…”

Making a heart: advances in understanding the mechanisms of cardiac development

“…Arrhythmogenic right ventricular (RV) cardiomyopathy was reported in a cardiac-restricted (SM22a) knockdown of the gene Rho-kinase. These mice developed desmosomal (cell–cell junction) abnormalities, myocardial fibrofatty changes, and ventricular arrhythmias similar to those found in humans [10 ■ ]. A cell polarity gene, VangI2 , was linked to cardiac outflow tract defects when knocked out specifically within the secondary heart field [responsible for development of the RV and the outflow tracts (OFT)] in the mouse.…”

Development of Novel Therapies for Cardiovascular Diseases by Clinical Application of Basic Research

“…In summary, the RhoA/Rho-kinase system plays a crucial role in EC dysfunction, VSMC contraction/proliferation, and inflammation. Roles for Rho-kinase in the development of cardiac hypertrophy, 38 fibrosis, 44 arrhythmogenic right ventricular cardiomyopathy (ARVC), 40 and PH 34,37 have been demonstrated.…”