Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone  

作　　者：Ya-han Liu Yan Liu Xu Zhang Li Fang Bei-lei Zhao Nan-ping Wang 

机构地区：[1]Key Laboratory of Molecular Cardiovascular Science,Ministry of Education [2]Institute of Cardiovascular Sciences,Peking University Health Science Center,Beijing 100191,China [3]East China Normal University Health Science Center,Shanghai 200241,China

出　　处：《Acta Pharmacologica Sinica》2022年第9期2302-2312,共11页中国药理学报（英文版）

基　　金：This study was supported by grants from the National Key R&D Program of China[2018YFA0800600];National Science Foundation of China[81830015,82170422 and 81670408].

摘　　要：Rosiglitazone(RSG)is a synthetic agonist of peroxisome proliferator-activated receptor-γ(PPARγ),which plays a central role in the regulation of metabolism.Meta-analyses have suggested that RSG is associated with increased cardiovascular risk.However,the mechanisms underlying such adverse cardiac effects are still poorly understood.Here,we found that activation of PPARγby RSG stimulated the endocannabinoid system(ECS),a membrane lipid signaling system,which induced cardiac hypertrophy.In neonatal rat cardiomyocytes,RSG increased the level of anandamide(AEA);upregulated the expression of N-acyl phosphatidylethanolamine phospholipase D(NapePLD),a key enzyme for AEA synthesis;and downregulated the expression of fatty acid amide hydrolase(FAAH),the enzyme responsible for the degradation of AEA.Importantly,PPARγactivation increased the expression of cannabinoid receptor type 1(CB1)through an identified binding site for PPARγin the CB1 promoter region.Moreover,both the in vitro and in vivo results showed that inhibition of the ECS by rimonabant,an antagonist of CB1,attenuated RSG-induced cardiac hypertrophy,as indicated by decreased expression of cardiac hypertrophy markers(ANP and BNP),deactivation of the mTOR pathway,and decreased cardiomyocyte size.Thus,these results demonstrated that the ECS functions as a novel target of PPARγand that the AEA/CB1/mTOR axis mediates RSG-induced cardiac remodeling.

关 键 词：peroxisome proliferator-activated receptor-γ ENDOCANNABINOIDS cardiac hypertrophy mammalian target of rapamycin 

分 类 号：R285.5[医药卫生—中药学]