The PPAR-γ antagonist GW9662 reduced lipid accumulation, fibrosis, and arrhythmogenic susceptibility in a mouse model of DSG2-linked arrhythmogenic cardiomyopathy.
Does the PPAR-γ antagonist GW9662 reduce fibrosis and arrhythmogenic remodeling in a Dsg2 F536C/F536C knock-in mouse model of arrhythmogenic cardiomyopathy?
PPAR-γ inhibition with GW9662 ameliorates structural and arrhythmogenic remodeling in a novel Dsg2 knock-in mouse model of arrhythmogenic cardiomyopathy, highlighting a potential therapeutic target.
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BACKGROUND: Arrhythmogenic cardiomyopathy is an inherited disorder characterized by fibro-fatty myocardial replacement and ventricular arrhythmias. Although desmosomal mutations such as desmoglein-2 ( DSG2 ) are well-established causes, the pathogenic mechanisms of specific missense variants remain incompletely defined. METHODS: We generated a physiologically relevant Dsg2 F536C/F536C knock-in mouse model using CRISPR/Cas9 to mimic the human DSG2 p.Phe531Cys mutation. Comprehensive phenotyping included histopathology, immunostaining, transcriptomic profiling, in vitro cardiomyocyte and fibroblast assays, in vivo imaging and ECG analysis, and ex vivo optical mapping. Therapeutic potential was assessed using the PPAR-γ (peroxisome proliferator-activated receptor gamma) antagonist GW9662. RESULTS: Dsg2 F536C/F536C mice developed progressive cardiac hypertrophy, interstitial fibrosis, lipid accumulation, and inducible ventricular arrhythmias following isoproterenol infusion and programmed electrical stimulation. These changes led to severe cardiac dysfunction and reduced survival. Mechanistically, the mutation caused reduced DSG2 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 and paracrine fibroblast activation via IL-6 (interleukin-6) and PDGF-BB (platelet-derived growth factor-BB) as key contributors to fibrotic remodeling. Optical mapping revealed prolonged and heterogeneous action potential duration, with both reentrant and focal ectopic mechanisms of ventricular tachycardia. Treatment with GW9662 attenuated lipid accumulation, fibrosis, reactive oxygen species production, and arrhythmogenic susceptibility. CONCLUSIONS: The Dsg2 F536C/F536C knock-in mouse is a genotype-specific arrhythmogenic cardiomyopathy model that links desmosomal dysfunction to metabolic remodeling, epicardial epithelial-to-mesenchymal transition, and electrophysiological instability. PPAR-γ inhibition ameliorated structural and arrhythmogenic remodeling, supporting PPAR-γ as a potential therapeutic target and advancing precision strategies for desmosome-related cardiomyopathies.
Yeh et al. (Tue,) reported a other. The PPAR-γ antagonist GW9662 reduced lipid accumulation, fibrosis, and arrhythmogenic susceptibility in a mouse model of DSG2-linked arrhythmogenic cardiomyopathy.
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