Reactivation of PPARαalleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acidβ-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy  

作　　者：Yubi Lin Ruonan Liu Yanling Huang Zhe Yang Jianzhong Xian Jingmin Huang Zirui Qiu Xiufang Lin Mengzhen Zhang Hui Chen Huadong Wang Jiana Huang Geyang Xu 

机构地区：[1]Department of Physiology,School of Medicine,Jinan University,Guangzhou 510632,China [2]The First Dongguan Affiliated Hospital,Guangdong Medical University Dongguan 523710,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,Cell-gene Therapy Translational Medicine Research Center,the Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510630,China [6]Department of Pathophysiology,School of Medicine,Jinan University,Guangzhou 510632,China [7]Reproductive Medicine Center,the Six Affiliated Hospital,Sun Yat-sen University,Guangzhou 51000,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第1期192-203,共12页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82170818,81770794,31401001);the Fundamental Research Funds for the Central Universities(21620423,China);the Science and Technology Project of Zhuhai(20191210E030072,China)。

摘　　要：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 CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.

关 键 词：Arrhythmogenic cardiomyopathy DESMOSOME Desmoglein2 Heart failure Lipid accumulation mTOR PPARa FA oxidation 

分 类 号：R541.7[医药卫生—心血管疾病]