Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Lin, Yenn‐Jiang; Liu, Ruonan; Huang, Yanling; Yang, Zhe; Xian, Jing; Huang, Jingmin; Qiu, Zirui; Lin, Xiufang; Zhang, Mengzhen; Chen, Hui; Wang, Hua-dong; Huang, Jiana; Xu, Geyang

doi:10.1016/j.apsb.2022.05.018

Cited by 12 publications

(10 citation statements)

References 62 publications

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“…Dsg2 mutation carriers display more severe heart muscle disease, which is associated with biventricular involvement and rapid evolution to end-stage heart failure [ 32 ]. In our previous study, we generated an ACM mouse model by cardiac-specific knockout of the DSG2 gene and discovered that downregulation of PPARα contributed to the impairment of fatty acid oxidation and, thus, to lipid accumulation in the DSG2 deletion-induced ACM [ 26 ]. However, whether downregulation of PPARα also contributes to the fibrosis in ACM was unsolved.…”

Section: Discussionmentioning

confidence: 99%

“…Fenofibrate alleviated myocardial inflammation and fibrosis in diabetic mice via PPARα receptor [ 43 ]. Our previous study showed that PPARα was downregulated in the heart of the Dsg2 deletion ACM model and reactivation of PPARα significantly alleviated the lipid accumulation and improved cardiac function in CS-Dsg2 −/− mice [ 26 ]. In the current study, we demonstrated that downregulation of PPARα also contributed to the cardiac fibrosis in the Dsg2 deletion-induced ACM model.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac-specific dsg2 gene knockout (CS-Dsg2 −/− ) on C57-based genetic backgrounds were successfully constructed by mating DSG2 flox with CKMM cre [ 26 ]. Mice were housed in standard plastic rodent cages and maintained in a regulated environment (24 °C, 12 h light and 12 h dark cycles with lights on at 7:00 a.m.).…”

Section: Methodsmentioning

confidence: 99%

“…Adeno-associated virus carrying GFP (AAV9-cTnT-GFP, 5 × 10 11 vg per mouse) was used as control. The mice were sacrificed 28 days after AAV injections [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…Fenofibrate alleviated myocardial inflammation and collagen deposition in Ang II-infused rats [ 25 ]. Recently, we reported that activation of PPARα reduced the cardiac lipid accumulation and restored cardiac function in ACM mice [ 26 ]. Although PPARα plays a critical role in lipid accumulation in ACM, the effects of PPARα on cardiac fibrosis in ACM is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Qiu

Zhao

Tian

et al. 2022

Cells

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Adeno-associated virus carrying GFP (AAV9-cTnT-GFP, 5 × 10 11 vg per mouse) was used as control. The mice were sacrificed 28 days after AAV injections [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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