Abstract 17399: Nuclear Plakoglobin Mediates Differentiation of Cardiac Progenitor Cells to Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an enigmatic disease characterized by fibro-fatty infiltration of the myocardium, particularly in the right ventricle. Molecular basis of adipocytic replacement of cardiac myocyte is not fully known. We have implicated suppression of the canonical Wnt signaling in the second heart field cardiac progenitors by nuclear plakoglobin (PG), a desmosome protein, in the pathogenesis of ARVC. However, the direct role of PG in a phenotypic switch from myogenesis to adipogenesis remains unestablished. To delineate the direct role of PG in adipogenesis in ARVC, we over-expressed and deleted PG in cardiac myocyte lineage in vivo. We also expressed a truncated PG, known to cause ARVC in humans, in the heart, as a control. Over-expression of wild type (WT) and mutant PG led to their nuclear localization. The WT but not the mutant PG also incorporated into desmosomes. The mutant PG exhibited reduced binding affinity to other desmosome proteins and predominantly was localized to cytosol and nucleus but not the membrane. Over-expression of WT and mutant PG led to excess adipocytes in the heart, cardiac dysfunction and premature death. FACS sorted c-Kit+/Sca1+ cells isolated from the hearts of transgenic PG mice showed increased adipogenesis and mRNA levels of adipogenic markers KLF15, BMP-7, IGFBP-5 and Wnt5B but decreased level of CTGF, an inhibitor of adipogenesis. Treatment with BIO, a known activator of the canonical Wnt signaling, reversed enhanced adipogenesis, in a dose-dependent manner. In contrast to the over-expressors, c-Kit+/Lin-/Flk- cells isolated from 12-day PG-null embryos showed suppressed adipogenesis and increased levels of canonical Wnt signaling markers, leading to embryonic lethality. These findings establish the direct role of nuclear PG in mediating transdifferentiation of cardiac progenitors cells to adipocytes in ARVC, a phenotypic switch that is induced by suppression of the canonical Wnt signaling and rescued upon activation of the canonical Wnt signaling.