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Published on: June 3, 2018
Activation of PPARα Ameliorates Cardiac Fibrosis in Dsg2-Deficient Arrhythmogenic Cardiomyopathy
Zirui Qiu1, Yawen Zhao1, Tian Tao1
1Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632, China.
Insights
Activating PPARα can alleviate cardiac fibrosis in arrhythmogenic cardiomyopathy (ACM), a genetic heart condition. This study investigated ACM mechanisms using a Dsg2 knockout mouse model, revealing a potential therapeutic target.
Area of Science:
- Cardiovascular Research
- Genetic Heart Diseases
- Molecular Mechanisms of Fibrosis
Background:
- Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by fibro-fatty replacement of cardiac myocytes.
- Current ACM therapies are primarily palliative.
- Mutations in desmosomal proteins, like Desmoglein-2 (Dsg2), cause approximately 50% of ACM cases.
Purpose of the Study:
- To investigate the mechanisms underlying cardiac fibrosis in ACM.
- To explore the role of Desmoglein-2 (Dsg2) in ACM pathogenesis.
- To identify potential therapeutic targets for ACM.
Main Methods:
- Utilized a cardiac-specific Dsg2 knockout (CS-Dsg2-/-) mouse model and wild-type (WT) controls.
- Assessed myocardial collagen volume fraction via histological analysis.
- Quantified fibrotic markers (α-SMA, Collagen I) and signaling molecules (STAT3, SMAD3, PPARα) using Western blot and qPCR.
Main Results:
- CS-Dsg2-/- mice exhibited increased cardiac fibrosis.
- PPARα deficiency and hyperactivation of STAT3/SMAD3 were observed in CS-Dsg2-/- hearts.
- Dsg2 silencing upregulated fibrotic markers in HL-1 cells; STAT3 silencing inhibited them.
- PPARα activation (fenofibrate or AAV9-Pparα) ameliorated cardiac fibrosis and reduced STAT3/SMAD3/AKT phosphorylation in CS-Dsg2-/- mice.
Conclusions:
- PPARα activation alleviates cardiac fibrosis in ACM.
- STAT3 and SMAD3 signaling pathways are implicated in Dsg2-related cardiac fibrosis.
- PPARα represents a potential therapeutic target for managing cardiac fibrosis in ACM.
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.
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