| First Author | Qiu Z | Year | 2022 |
| Journal | Cells | Volume | 11 |
| Issue | 20 | PubMed ID | 36291052 |
| Mgi Jnum | J:345118 | Mgi Id | MGI:7383362 |
| Doi | 10.3390/cells11203184 | Citation | Qiu Z, et al. (2022) Activation of PPARalpha Ameliorates Cardiac Fibrosis in Dsg2-Deficient Arrhythmogenic Cardiomyopathy. Cells 11(20) |
| abstractText | 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 alpha-SMA and Collagen I as well as signal transducers such as STAT3, SMAD3, and PPARalpha were measured by Western blot and quantitative real-time PCR. RESULTS: Increased cardiac fibrosis was observed in CS-Dsg2(-/-) mice according to Masson staining. PPARalpha deficiency and hyperactivation of STAT3 and SMAD3 were observed in the myocardium of CS-Dsg2(-/-) mice. The biomarkers of fibrosis such as alpha-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 PPARalpha by fenofibrate or AAV9-Pparalpha improved the cardiac fibrosis and decreased the phosphorylation of STAT3, SMAD3, and AKT in CS-Dsg2(-/-) mice. CONCLUSIONS: Activation of PPARalpha alleviates the cardiac fibrosis in ACM. |
