Celastrol is a quinone methide triterpenoid extracted from the root bark of Tripterygium wilfordii Hook F,and it exhibits extensive biological activities such as anti-cancer effects.However,narrow therapeutic window together with undesired side effects limit its clinical application.In this study,we explore celastrol's cardiotoxicity using the methods of histology and cell biology.The results show that celastrol administration dose-dependently induces cardiac dysfunction in mice as manifested by left ventricular dilation,myocardial interstitial fibrosis,and cardio-myocyte hypertrophy.Exposure to celastrol greatly decreases neonatal rat ventricular myocyte(NRVM)viability and promotes its apoptosis.More importantly,we demonstrate that celastrol exerts its pro-apoptotic effects through endoplasmic reticulum(ER)stress and unfolded protein response.Furthermore,siRNA targeting C/EBP homologous protein,a pivotal component of ER stress-mediated apoptosis,effectively prevents the pro-apoptotic effect of celastrol.Taken together,our results demonstrate the potential cardiotoxicity of celastrol and a direct involvement of ER stress in the celastrol-induced apoptosis of NRVMs.Thus,we recommend careful evaluation of celastrol's cardiovascular effects when using it in the clinic.

Zhong Chen;Zhong Zhuang;Chen Meng;Zhonghua Zhu;Yin Zhang;Zhao Zhang

Jiangsu Key Laboratory for Molecular and Medical Biotechnology,College of Life Sciences,Nanjing Normal University,Nanjing 210023,China;Jiangsu Key Laboratory of Molecular Medicine of the School of Medicine,Nanjing University,Nanjing 210093,China;School of Food Science and Pharmaceutical Engineering,Nanjing Normal University,Nanjing 210023,China

生物化学与生物物理学报（英文版）

[1]Zhong Chen;Zhong Zhuang;Chen Meng;Zhonghua Zhu;Yin Zhang;Zhao Zhang-.Induction of the ER stress response in NRVMs is linked to cardiotoxicity caused by celastrol)[J].生物化学与生物物理学报（英文版）,2022(08):1180-1192

NRVMs,methide,NRVM

Induction,ER,stress,response,linked,cardiotoxicity,caused,by,celastrol,Celastrol,quinone,triterpenoid,extracted,from,root,bark,Tripterygium,wilfordii,Hook,exhibits,extensive,biological,activities,such,anti,cancer,effects,However,narrow,therapeutic,window,together,undesired,side,limit,clinical,application,this,study,explore,using,methods,histology,cell,biology,results,show,that,administration,dose,dependently,induces,cardiac,dysfunction,mice,manifested,left,ventricular,dilation,myocardial,interstitial,fibrosis,myocyte,hypertrophy,Exposure,greatly,decreases,neonatal,viability,promotes,apoptosis,More,importantly,demonstrate,exerts,apoptotic,through,endoplasmic,reticulum,unfolded,protein,Furthermore,siRNA,targeting,EBP,homologous,pivotal,component,mediated,effectively,prevents,Taken,our,potential,direct,involvement,induced,Thus,recommend,careful,evaluation,cardiovascular,when

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