In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. 12 ( 2011-12-09), p. 1342-1353
Abstract:
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 (PG WT ) or a truncated (PG TR ), known to cause ARVC, in the heart; and PG null (PG −/− ) embryos. PG WT and PG TR mice exhibited fibro-adiposis, cardiac dysfunction, and premature death. Subcellular protein fractionation and immunofluorescence showed nuclear localization of PG WT and PG TR and reduced membrane localization of PG TR . Coimmunoprecipitation showed reduced binding of PG TR but not PG WT to desmosome proteins DSP and DSG2. Transgene PG WT and PG TR were expressed in c-Kit + :Sca1 + cardiac progenitor cells (CPCs) isolated from the hearts of PG WT and PG TR 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.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.111.255075
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2011
detail.hit.zdb_id:
1467838-X
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