ABSTRACT: Background:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder characterized by fibrofatty myocardial replacement and ventricular arrhythmias. While desmosomal gene mutations, including DSG2, are well-established causes, the mechanisms by which specific missense mutations contribute to disease progression remain poorly understood. Methods:We generated a physiologically relevant Dsg2F536C knock-in (KI) mouse model using CRISPR/Cas9 to mimic the human DSG2p.Phe531Cys mutation. Comprehensive phenotyping included histopathology, immunostaining, transcriptomic profiling, in vitro cardiomyocyte and fibroblast assays, in vivo image and ECG analysis, and ex vivo optical mapping. Therapeutic potential was assessed using the PPAR-γ antagonist GW9662. Results:Dsg2F536C/F536C mice developed progressive cardiac hypertrophy, interstitial fibrosis, lipid accumulation, and inducible ventricular arrhythmias following isoproterenol infusion and programmed electrical stimulation. These changes resulted in severe cardiac dysfunction and were associated with reduced survival. Mechanistically, the mutation led to decreased DSG2 expression and nuclear accumulation of β-catenin and PPAR-γ, promoting triacylglycerol biosynthesis, oxidative stress, cardiomyocyte death, and calcium-handling abnormalities. We also identified activation of epicardial epithelial-to-mesenchymal transition (EMT) and paracrine fibroblast activation via IL-6 and PDGF-BB as key contributors to fibrotic remodeling. Optical mapping revealed prolonged and heterogeneous action potential duration and demonstrated both reentrant and focal ectopic mechanisms of ventricular tachycardia. Treatment with GW9662 attenuated lipid accumulation, fibrosis, ROS production, and arrhythmogenic susceptibility. Conclusions:This study establishesdsg2F536C KI mice as a robust genotype-specific ARVC model and uncovers a mechanistic link between desmosomal dysfunction, metabolic remodeling, epicardial EMT, and arrhythmia. Pharmacological inhibition of PPAR-γ mitigated structural and electrophysiological abnormalities, identifying it as a promising therapeutic target. These findings support a precision medicine framework for the treatment of desmosome-related cardiomyopathies.
