Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy.
10.1016/j.apsb.2022.05.018
- Author:
Yubi LIN
1
;
Ruonan LIU
2
;
Yanling HUANG
2
;
Zhe YANG
3
;
Jianzhong XIAN
3
;
Jingmin HUANG
2
;
Zirui QIU
2
;
Xiufang LIN
3
;
Mengzhen ZHANG
4
;
Hui CHEN
5
,
6
;
Huadong WANG
7
;
Jiana HUANG
8
;
Geyang XU
2
Author Information
1. The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
2. Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China.
3. The Cardiovascular Center, Department of Cardiology, Interventional Medical Center, Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
4. Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangzhou 510080, China.
5. Biotherapy Center
6. Cell-gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
7. Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510632, China.
8. Reproductive Medicine Center, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou 51000, China.
- Publication Type:Journal Article
- Keywords:
Arrhythmogenic cardiomyopathy;
Desmoglein2;
Desmosome;
FA oxidation;
Heart failure;
Lipid accumulation;
PPARα;
mTOR
- From:
Acta Pharmaceutica Sinica B
2023;13(1):192-203
- CountryChina
- Language:English
-
Abstract:
Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.
