Activation of PPARα Ameliorates Cardiac Fibrosis in Dsg2-Deficient Arrhythmogenic Cardiomyopathy

HIGHLIGHTS: Cardiac-specific Dsg2 deletion induces excessive cardiac fibrosis in mice. Fenofibrate alleviates cardiac fibrosis in CS-Dsg2(−/−) mice. Cardiac-specific activation of PPARα ameliorates cardiac fibrosis in CS-Dsg2(−/−) mice. The inhibitory effect of PPARα on cardiac fibrosis is mediated by STAT3 and TGF-β /SMAD3 signaling. PPARα is a promising target for the intervention of ACM by ameliorating cardiac fibrosis. ABSTRACT: Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by progressive fibro-fatty replacement of cardiac myocytes. Up to now, the existing therapeutic modalities for ACM are mostly palliative. About 50% of ACM is caused by mutations in genes encoding desmosomal proteins including Desmoglein-2 (Dsg2). In the current study, the cardiac fibrosis of ACM and its underlying mechanism were investigated by using a cardiac-specific knockout of Dsg2 mouse model. Methods: Cardiac-specific Dsg2 knockout (CS-Dsg2(−/−)) mice and wild-type (WT) mice were respectively used as the animal model of ACM and controls. The myocardial collagen volume fraction was determined by histological analysis. The expression levels of fibrotic markers such as α-SMA and Collagen I as well as signal transducers such as STAT3, SMAD3, and PPARα were measured by Western blot and quantitative real-time PCR. Results: Increased cardiac fibrosis was observed in CS-Dsg2(−/−) mice according to Masson staining. PPARα deficiency and hyperactivation of STAT3 and SMAD3 were observed in the myocardium of CS-Dsg2(−/−) mice. The biomarkers of fibrosis such as α-SMA and Collagen I were upregulated after gene silencing of Dsg2 in HL-1 cells. Furthermore, STAT3 gene silencing by Stat3 siRNA inhibited the expression of fibrotic markers. The activation of PPARα by fenofibrate or AAV9-Pparα improved the cardiac fibrosis and decreased the phosphorylation of STAT3, SMAD3, and AKT in CS-Dsg2(−/−) mice. Conclusions: Activation of PPARα alleviates the cardiac fibrosis in ACM.