SZC-6,a small-molecule activator of SIRT3,attenuates cardiac hypertrophy in mice  

作　　者：Ze-yu Li Guo-qing Lu Jing Lu Pan-xia Wang Xiao-lei Zhang Yong Zou Pei-qing Liu 

机构地区：[1]National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation,Guangdong Province Engineering Laboratoty for Druggability and New Drug Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

出　　处：《Acta Pharmacologica Sinica》2023年第3期546-560,共15页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(U21A20419,82173808,82150204,81872860,82104157);Natural Science Foundation of Guangdong Province(2021B1515020100,2022A1515012322,2016A030311033);the Basic and Applied Basic Research Foundation of Guangdong Province(2020A1515410003);National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004);Guangzhou Basic and Applied Basic Research Project(202102020173);Guangdong Provincial Key Laboratory of Construction Foundation(2017B030314030);the Fundamental Research Funds for the Central Universities,Sun Yat-sen University(22qntd4510).

摘　　要：Sirtuin3(SIRT3),a class III histone deacetylase,is implicated in various cardiovascular diseases as a novel therapeutic target.SIRT3 has been proven to be cardioprotective in a model of Ang II-induced cardiac hypertrophy.However,a few small-molecule compounds targeting deacetylases could activate SIRT3.In this study,we generated a novel SIRT3 activator,3-(2-bromo-4-hydroxyphenyl)-7-hydroxy-2H-chromen-2-one(SZC-6),through structural optimization of the first SIRT3 agonist C12.We demonstrated that SZC-6 directly bound to SIRT3 with Kd value of 15μM,and increased SIRT3 deacetylation activity with EC50 value of 23.2±3.3µM.In neonatal rat cardiomyocytes(NRCMs),pretreatment with SZC-6(10,20,40µM)dose-dependently attenuated isoproterenol(ISO)-induced hypertrophic responses.Administration of SZC-6(20,40 and 60 mg·kg^(−1)·d^(−1),s.c.)for 2 weeks starting from one week prior ISO treatment dose-dependently reversed ISO-induced impairment of diastolic and systolic cardiac function in wild-type mice,but not in SIRT3 knockdown mice.We showed that SZC-6(10,20,40µM)dose-dependently inhibited cardiac fibroblast proliferation and differentiation into myofibroblasts,which was abolished in SIRT3-knockdown mice.We further revealed that activation of SIRT3 by SZC-6 increased ATP production and rate of mitochondrial oxygen consumption,and reduced ROS,improving mitochondrial function in ISO-treated NRCMs.We also found that SZC-6 dose-dependently enhanced LKB1 phosphorylation,thereby promoting AMPK activation to inhibit Drp1-dependent mitochondrial fragmentation.Taken together,these results demonstrate that SZC-6 is a novel SIRT3 agonist with potential value in the treatment of cardiac hypertrophy partly through activation of the LKB1-AMPK pathway.

关 键 词：cardiac hypertrophy SIRT3 SZC-6 oxidative stress mitochondrial malfunction LKB1-AMPK pathway 

分 类 号：R589.2[医药卫生—内分泌]