Nuclear Plakoglobin Is Essential for Differentiation of Cardiac Progenitor Cells to Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy

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Abstract

Rationale:

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease of desmosome proteins characterized by fibroadipogenesis in the myocardium. We have implicated signaling properties of junction protein plakoglobin (PG) in the pathogenesis of ARVC.

Objective:

To delineate the pathogenic role of PG in adipogenesis in ARVC.

Methods and Results:

We generated mice overexpressing PG, either a wildtype (PGWT) or a truncated (PGTR), known to cause ARVC, in the heart; and PG null (PG−/−) embryos. PGWT and PGTR mice exhibited fibro-adiposis, cardiac dysfunction, and premature death. Subcellular protein fractionation and immunofluorescence showed nuclear localization of PGWT and PGTR and reduced membrane localization of PGTR. Coimmunoprecipitation showed reduced binding of PGTR but not PGWT to desmosome proteins DSP and DSG2. Transgene PGWT and PGTR were expressed in c-Kit+:Sca1+ cardiac progenitor cells (CPCs) isolated from the hearts of PGWT and PGTR by fluorescence activated cell sorting. CPCs isolated from the transgenic hearts showed enhanced adipogenesis, increased levels of adipogenic factors KLF15, C/EBP-α and noncanonical Wnt5b, and reduced level of CTGF, an inhibitor of adipogenesis. Treatment with BIO activated the canonical Wnt signaling, reversed the proadipogenic transcriptional switch and prevented adipogenesis in a dose-dependent manner. Moreover, c-Kit+ CPCs, isolated from PG−/− embryos, were resistant to adipogenesis, expressed high mRNA levels of CTGF and other canonical Wnt signaling targets.

Conclusions:

Nuclear PG provokes adipogenesis in c-Kit+ CPCs by repressing the canonical Wnt signaling and inducing a proadipogenic gene expression. The findings suggest that adipocytes in ARVC, at least in part, originate from c-Kit+ CPCs.

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