PMID- 36815030
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230224
IS  - 2211-3835 (Print)
IS  - 2211-3843 (Electronic)
IS  - 2211-3835 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Jan
TI  - Reactivation of PPARalpha alleviates myocardial lipid accumulation and cardiac 
      dysfunction by improving fatty acid beta-oxidation in Dsg2-deficient arrhythmogenic 
      cardiomyopathy.
PG  - 192-203
LID - 10.1016/j.apsb.2022.05.018 [doi]
AB  - 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) 
      beta-oxidation resulted from impaired mammalian target of rapamycin (mTOR) 
      signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the 
      FA beta-oxidation pathway in CS-Dsg2 (-/-) mice. Reactivation of PPARalpha by 
      fenofibrate or AAV9-Pparalpha significantly alleviated the lipid accumulation and 
      restored cardiac function. Our results suggest that impaired 
      mTOR-4EBP1-PPARalpha-dependent FA beta-oxidation contributes to myocardial lipid 
      accumulation in ACM and PPARalpha may be a potential target for curative treatment of 
      ACM.
CI  - (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, 
      Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
FAU - Lin, Yubi
AU  - Lin Y
AD  - The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 
      523710, China.
FAU - Liu, Ruonan
AU  - Liu R
AD  - Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, 
      China.
FAU - Huang, Yanling
AU  - Huang Y
AD  - Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, 
      China.
FAU - Yang, Zhe
AU  - Yang Z
AD  - 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.
FAU - Xian, Jianzhong
AU  - Xian J
AD  - 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.
FAU - Huang, Jingmin
AU  - Huang J
AD  - Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, 
      China.
FAU - Qiu, Zirui
AU  - Qiu Z
AD  - Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, 
      China.
FAU - Lin, Xiufang
AU  - Lin X
AD  - 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.
FAU - Zhang, Mengzhen
AU  - Zhang M
AD  - Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's 
      Hospital, Guangzhou 510080, China.
FAU - Chen, Hui
AU  - Chen H
AD  - Biotherapy Center; Cell-gene Therapy Translational Medicine Research Center, the 
      Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
FAU - Wang, Huadong
AU  - Wang H
AD  - Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Huang, Jiana
AU  - Huang J
AD  - Reproductive Medicine Center, the Six Affiliated Hospital, Sun Yat-sen 
      University, Guangzhou 51000, China.
FAU - Xu, Geyang
AU  - Xu G
AD  - Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, 
      China.
LA  - eng
PT  - Journal Article
DEP - 20220521
PL  - Netherlands
TA  - Acta Pharm Sin B
JT  - Acta pharmaceutica Sinica. B
JID - 101600560
PMC - PMC9939300
OTO - NOTNLM
OT  - Arrhythmogenic cardiomyopathy
OT  - Desmoglein2
OT  - Desmosome
OT  - FA oxidation
OT  - Heart failure
OT  - Lipid accumulation
OT  - PPARalpha
OT  - mTOR
COIS- The authors have no conflicts of interest to declare.
EDAT- 2023/02/24 06:00
MHDA- 2023/02/24 06:01
PMCR- 2022/05/21
CRDT- 2023/02/23 02:14
PHST- 2022/01/06 00:00 [received]
PHST- 2022/03/27 00:00 [revised]
PHST- 2022/04/02 00:00 [accepted]
PHST- 2023/02/23 02:14 [entrez]
PHST- 2023/02/24 06:00 [pubmed]
PHST- 2023/02/24 06:01 [medline]
PHST- 2022/05/21 00:00 [pmc-release]
AID - S2211-3835(22)00240-4 [pii]
AID - 10.1016/j.apsb.2022.05.018 [doi]
PST - ppublish
SO  - Acta Pharm Sin B. 2023 Jan;13(1):192-203. doi: 10.1016/j.apsb.2022.05.018. Epub 
      2022 May 21.