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Published on: June 3, 2018
Targeting PPAR-γ Reduces Fibrosis and Arrhythmogenic Remodeling in DSG2-Linked Arrhythmogenic Cardiomyopathy
Yung-Hsin Yeh1, Yu-Shien Ko2, Yi-Hsin Chan2
1School of Traditional Chinese Medicine (Y.-H.C.), College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Insights
A new mouse model reveals how desmoglein-2 mutations cause arrhythmogenic cardiomyopathy. PPAR-γ inhibition offers a potential therapeutic strategy for this inherited heart disorder.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition characterized by fibro-fatty tissue replacement in the ventricles, leading to arrhythmias.
- Desmosomal gene mutations, like those in desmoglein-2 (DSG2), are known causes of ACM, but the precise mechanisms of specific variants are not fully understood.
Purpose of the Study:
- To create and characterize a novel mouse model mimicking a specific human DSG2 missense mutation (p.Phe531Cys) to elucidate pathogenic mechanisms in ACM.
- To investigate the therapeutic potential of targeting PPAR-γ (peroxisome proliferator-activated receptor gamma) in this model.
Main Methods:
- Generated a Dsg2F536C/F536C knock-in mouse model using CRISPR/Cas9 technology.
- Conducted comprehensive phenotyping including histopathology, molecular analyses, cardiomyocyte and fibroblast assays, in vivo imaging, ECG, and ex vivo optical mapping.
- Assessed therapeutic effects of the PPAR-γ antagonist GW9662.
Main Results:
- Dsg2F536C/F536C mice exhibited progressive cardiac hypertrophy, fibrosis, lipid accumulation, and inducible ventricular arrhythmias, leading to severe cardiac dysfunction and reduced survival.
- The mutation disrupted DSG2 function, altered β-catenin and PPAR-γ localization, promoted lipid synthesis, oxidative stress, and cardiomyocyte death.
- Epicardial epithelial-to-mesenchymal transition and fibroblast activation were identified as key drivers of fibrosis, while optical mapping revealed prolonged action potentials and reentrant/focal arrhythmias.
Conclusions:
- The Dsg2F536C/F536C mouse model effectively recapitulates genotype-specific ACM, linking desmosomal dysfunction to metabolic changes, EMT, and electrical instability.
- PPAR-γ inhibition demonstrated efficacy in ameliorating structural and arrhythmogenic remodeling, highlighting PPAR-γ as a promising therapeutic target for desmosome-related cardiomyopathies.
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 Dsg2F536C/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:
Dsg2F536C/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 Dsg2F536C/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.
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