title: Activation of SIRT3 attenuates triptolide-induced toxicity through closing mitochondrial permeability transition pore in cardiomyocytes.
abstract: Triptolide (TP), an active component of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), has multiple pharmacological effects. However, the severe toxicity of TP greatly restricts its clinical applications. Although TP exposure causes serious heart injury, the mechanism underlying TP-induced cardiotoxicity has rarely been investigated. In previous studies, we found that TP-induced oxidative stress was involved in the mitochondria-dependent apoptosis of cardiomyocytes. Opening of the mitochondrial permeability transition pore (mPTP) is the key to the mitochondrial dysfunction in cardiac toxicity. The aim of this study was to investigate the potential cardioprotective effects of sirtuin 3 (SIRT3) on the mPTP. In the present study, the cytotoxicity of TP was accompanied by the up-regulation of the SIRT3 protein level and its rapid aggregation in nuclei and mitochondria. The SIRT3-FOXO3 signaling pathway was activated simultaneously, resulting in increased transcription of manganese superoxide dismutase (MnSOD) and catalase (CAT) for the elimination of reactive oxygen species (ROS). In addition, augmentation of the SIRT3 level via the overexpression plasmid SIRT3-Flag provided resistance to TP-induced cellular damage, whereas knocking down the SIRT3 level via siRNA accelerated the damage. Because it is an activator of SIRT3, the protective effect of resveratrol was also evaluated in H9c2 cells. In conclusion, the current results suggest that activation of SIRT3 substantially ameliorates the detrimental effects of TP by closing the mPTP.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Zhewen
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Kong
authors.affiliation: Laboratory Animals Center, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Feihai
authors.initials: F
authors.lastname: Shen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Laboratory Animals Center, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: hzhiying@mail.sysu.edu.cn.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004224:Diterpenes / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010616:Phenanthrenes / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C000607791:SIRT3 protein, rat; C001899:triptolide; D002374:Catalase; D013482:Superoxide Dismutase; D037761:Sirtuins
keywords: Cardioprotection; Mitochondrial permeability transition pore; SIRT3; Triptolide