Arrhythmogenic right ventricular cardiomyopathy: moving toward mechanism
Calum A. MacRae, … , Walter Birchmeier, Ludwig Thierfelder
Calum A. MacRae, … , Walter Birchmeier, Ludwig Thierfelder
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1825-1828. https://doi.org/10.1172/JCI29174.
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Arrhythmogenic right ventricular cardiomyopathy: moving toward mechanism

Abstract

Mutations in genes encoding desmosomal proteins have been identified as the major cause of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC), in which the right ventricle is “replaced” by fibrofatty tissue, resulting in lethal arrhythmias. In this issue of the JCI, Garcia-Gras et al. demonstrate that cardiac-specific loss of the desmosomal protein desmoplakin is sufficient to cause nuclear translocation of plakoglobin, upregulation of adipogenic genes in vitro, and a shift from a cardiomyocyte to an adipocyte cell fate in vivo (see the related article beginning on page 2012). This evidence for potential Wnt/β-catenin signaling defects sets the scene for a comprehensive exploration of the contributions of this pathway to the pathophysiology of ARVC, not only through perturbation of cardiac patterning and development, but also through effects on myocardial differentiation and physiology.

Authors

Calum A. MacRae, Walter Birchmeier, Ludwig Thierfelder

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Figure 1

Cardiac-specific restriction of the desmosomal protein desmoplakin causes nuclear localization of plakoglobin and reduced Wnt/β-catenin signaling, recapitulating human ARVC.

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Cardiac-specific restriction of the desmosomal protein desmoplakin cause...
(A) ARVC predominantly affects the right ventricle of the heart. (B) The intercalated discs of cardiac myocytes are characterized by gap junctions, adherens junctions, and desmosomes. (C) Cell-cell adhesion is largely dependent on interaction of intracellular components of the desmosomal plaque such as desmoplakin and plakoglobin. (D) In this issue of the JCI, Garcia-Gras et al. (16) report that heterozygous cardiac desmoplakin-deficient mice show nuclear localization of plakoglobin and reduced Wnt/β-catenin signaling. This causes increased expression of adipogenic and fibrogenic genes in vitro, abnormal cardiac adipose tissue and fibrosis in vivo, and ventricular arrhythmias similar to human ARVC. Interactions between signaling defects and mechanical stresses are likely to be involved in the genesis of the final phenotype.