Induction of the ER stress response in NRVMs is linked to cardiotoxicity caused by celastrol  

作　　者：Zhong Chen Zhong Zhuang Chen Meng Zhonghua Zhu Yin Zhang Zhao Zhang 

机构地区：[1]Jiangsu Key Laboratory for Molecular and Medical Biotechnology,College of Life Sciences,Nanjing Normal University,Nanjing 210023,China [2]School of Food Science and Pharmaceutical Engineering,Nanjing Normal University,Nanjing 210023,China [3]Jiangsu Key Laboratory of Molecular Medicine of the School of Medicine,Nanjing University,Nanjing 210093,China

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第8期1180-1192,共13页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grants from the National Natural Science Foundation of China(Nos.30871228 and 31171302);the Priority Academic Development Program(No.164320H106),and the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine of the Jiangsu Institute of Higher Education.

摘　　要：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 cardiomyocyte 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.

关 键 词：CARDIOTOXICITY CELASTROL endoplasmic reticulum stress neonatal rat ventricular myocytes 

分 类 号：O62[理学—有机化学]