S-nitrosylation of Hsp90 promotes cardiac hypertrophy in mice through GSK3βsignaling  

作　　者：Shuang Zhao Tian-yu Song Zi-yu Wang Jie Gao Jia-wei Cao Lu-lu Hu Zheng-rong Huang Li-ping Xie Yong Ji 

机构地区：[1]Key Laboratory of Cardiovascular and Cerebrovascular Medicine,Nanjing Medical University,Nanjing,210029,China [2]Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing,210029,China [3]Department of Cardiology,The First Affiliated Hospital of Xiamen University,Xiamen,361003,China

出　　处：《Acta Pharmacologica Sinica》2022年第8期1979-1988,共10页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(grant nos.82030013,82070278,91639204,81870183);National Key Research and Development Program of China(2019YFA0802704);China Postdoctoral Science Foundation(2020M681667).

摘　　要：Cardiac hypertrophy,as one of the major predisposing factors for chronic heart failure,lacks effective interventions.Exploring the pathogenesis of cardiac hypertrophy will reveal potential therapeutic targets.S-nitrosylation is a kind of posttranslational modification that occurs at active cysteines of proteins to mediate various cellular processes.We here identified heat shock protein 90(Hsp90)as a highly S-nitrosylated target in the hearts of rodents with hypertrophy,and the role of Hsp90 in cardiac hypertrophy remains undefined.The S-nitrosylation of Hsp90(SNO-Hsp90)levels were elevated in angiotensinⅡ(AngⅡ)-or phenylephrine(PE)-treated neonatal rat cardiomyocytes(NRCMs)in vitro as well as in cardiomyocytes isolated from mice subjected to transverse aortic constriction(TAC)in vivo.We demonstrated that the elevated SNO-Hsp90 levels were mediated by decreased S-nitrosoglutathione reductase(GSNOR)expression during cardiac hypertrophy,and delivery of GSNOR adeno-associated virus expression vectors(AAV9-GSNOR)decreased the SNO-Hsp90 levels to attenuate cardiac hypertrophy.Mass spectrometry analysis revealed that cysteine 589(Cys589)might be the S-nitrosylation site of Hsp90.Delivery of the mutated AAV9-Hsp90-C589A inhibited SNO-Hsp90 levels and attenuated cardiac hypertrophy.We further revealed that SNO-Hsp90 led to increased interaction of glycogen synthase kinase 3β(GSK3β)and Hsp90,leading to elevated GSK3βphosphorylation and decreased eIF2Bs phosphorylation,thereby aggravating cardiac hypertrophy.Application of GSK3βinhibitor TWS119 abolished the protective effect of Hsp90-C589A mutation in AngⅡ-treated NRCMs.In conclusion,this study demonstrates a critical role of SNO-Hsp90 in cardiac hypertrophy,which may be of a therapeutic target for cardiac hypertrophy treatment.

关 键 词：cardiac hypertrophy S-NITROSYLATION HSP90 GSK3Β neonatal rat cardiomyocytes transverse aortic constriction mice 

分 类 号：R965[医药卫生—药理学]