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

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.

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls

“…It has been reported that alterations in transmembrane proteins and desmosomes may lead to changes in cell signalling, and to adipogenic/fibrogenic proliferation or an imbalance of fatty acid oxidation due to changes in PPAR molecules. 30,31 In our study, we did not find a change in the mRNA expression of any …”

Giant Cardiac Lipoma: Refined Hypothesis Proposes Invagination from Extracardiac to Intracardiac Sites

“…17 Cardiac adipocytes have been attributed to differentiation of cardiac precursor cells in patients who have arrhythmogenic right ventricular cardiomyopathy. 6 On the other hand, large intracardiac lipomas-particularly those in the right atrium-have never been completely explained. Primary rhabdomyosarcomas of the heart have never been well documented, which suggests that differentiation of cardiac stem cells might not, by itself, account for all primary tumors of the heart, or for these cells' effective participation in myocardial regeneration after injury.…”

“…2,3 Cardiac lipomas are isolated cases among larger series of cardiac neoplasms. 4 Chen and colleagues 5 and Lombardi and associates 6 proposed that primary tumors of the heart arise from gene mutations and the proliferation of various cell types in the myocardium; however, no unifying hypothesis regarding the development of intra-atrial giant lipomas has been proved. Modern imaging techniques, including improvements in echocardiography, have simplified diagnosis 7 ; the addition of spiral computed tomography (CT) and magnetic resonance imaging (MRI) adds clarity to the extent of these tumors.…”

“…Adipogenesis after injury and cardiomyopathy is being investigated. 5,6 Modern theories have heretofore focused on fibroadipocytic replacements of myocytes within the intraventricular septum or ventricles.…”

Normalization of Naxos plakoglobin levels restores cardiac function in mice

“…In addition to LOF mouse models, gain-of-function (GOF) transgenic mice and zebrafish overexpressing the truncated plakoglobin have been generated (6,7). In GOF models, many characteristic signs of Naxos cardiomyopathy are also observed, including fibrofatty replacement of cardiomyocytes.…”