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Toxicol In Vitro. 2016 Aug;34:128-137. doi: 10.1016/j.tiv.2016.03.020. Epub 2016 Apr 8.

Activation of SIRT3 attenuates triptolide-induced toxicity through closing mitochondrial permeability transition pore in cardiomyocytes.

Author information

1
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
2
Laboratory Animals Center, Sun Yat-sen University, Guangzhou 510006, PR China.
3
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.

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.

KEYWORDS:

Cardioprotection; Mitochondrial permeability transition pore; SIRT3; Triptolide

PMID:
27064125
DOI:
10.1016/j.tiv.2016.03.020
[Indexed for MEDLINE]

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