Abstract 3400: Cardiac-Restricted Deletion Of Desmoplakin In Mice Recapitulates The Phenotype of Human Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) is genetic disease that commonly manifests with cardiac arrhythmias and sudden cardiac death and occasionally with heart failure. The pathological hallmark of ARVC is adipocytic replacement of cardiac myocytes occurring in conjunction with fibrosis and myocyte apoptosis. Mutations in 4 genes encoding desmosomal proteins desmoplakin (DP), plakoglobin (PG), plakophilin 2 and desmoglein 2 have been identified in patients with ARVC. However, the pathogenesis of cardiac phenotype in ARVC is unknown. Based on cell culture studies, we have implicated suppressed canonical Wnt signaling by nuclear PG as a responsible for the pathogenesis of ARVC phenotype. To test this hypothesis in vivo, we utilized the LoxP-Cre recombinase technology to delete Dsp, encoding DP, specifically in the heart in mice. Cre-mediated deletion of Dsp led to high embryonic lethality in homozygous state (DP−/−) because of poor cardiac morphogenesis but normal embryonic development in heterozygous (DP+/−) state. The DP+/− mice exhibited an age-dependent penetrance, including 20% mortality by 6 months of age. Ventricular/body weight ratio was increased by 2 fold in DP+/− and 3-fold in DP−/− mice. Immunoblotting on cell protein subfractions with an anti-PG antibody showed increased level of PG in the nucleus in DP+/− mice. Semi-quantitative RT-PCR showed increased expression levels of adipogenic markers C/EBP-α and adiponectin and decreased expression levels of the canonical Wnt signaling target genes c-myc and cyclin D1. The DP-deficient mice exhibited excess fibro-adipocytic replacement of the myocardium, comprising up to 25% of the myocardium and increased myocyte apoptosis, both more prominent in DP−/− mice. Echocardiography showed enlarged cardiac chambers and systolic dysfunction. Electrophysiological studies showed spontaneous and inducible ventricular tachycardia. The collective results establish cardiac-restricted DP-deficient mouse as a model for human ARVC and implicate suppressed canonical Wnt signaling as a mechanism for the pathogenesis of the phenotype.