Suppression of Canonical Wnt/beta-catenin Signaling by Nuclear Plakoglobin Recapitulates Phenotype of Arrhythmogenic Right Ventricular Cardiomyopathy

J Clin Invest. 2006 Jul;116(7):2012-21. doi: 10.1172/JCI27751.

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / physiology
  • Animals
  • Arrhythmogenic Right Ventricular Dysplasia* / metabolism
  • Arrhythmogenic Right Ventricular Dysplasia* / pathology
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Desmoplakins / genetics
  • Desmoplakins / metabolism*
  • Electrophysiology
  • Embryo, Mammalian / anatomy & histology
  • Embryo, Mammalian / physiology
  • Heart Atria / cytology
  • Heart Atria / pathology
  • Humans
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / physiology
  • Phenotype
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / physiology*
  • TCF Transcription Factors / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*
  • gamma Catenin / genetics
  • gamma Catenin / metabolism*

Substances

  • Desmoplakins
  • RNA, Small Interfering
  • TCF Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • gamma Catenin