SIRT3
烟酰胺腺嘌呤二核苷酸磷酸
缺血
氧化应激
谷胱甘肽
烟酰胺腺嘌呤二核苷酸
锡尔图因
活性氧
再灌注损伤
药理学
化学
缺血预处理
内分泌学
内科学
医学
NAD+激酶
线粒体
IDH2型
生物化学
IDH1
酶
突变体
氧化酶试验
基因
作者
Liang Ma,Hongtao Shi,Yang Li,Wei Gao,Junjie Guo,Jianbing Zhu,Dong Zheng,Aijun Sun,Yunzeng Zou,Junbo Ge
标识
DOI:10.1016/j.scib.2021.04.008
摘要
To test the hypothesis that transient nonischemic stimulation of hypertrophy would render the heart resistant to subsequent ischemic stress, short-term transverse aortic constriction (TAC) was performed in mice and then withdrawn for several days by aortic debanding, followed by subsequent myocardial exposure to ischemia/reperfusion (I/R). Following I/R injury, the myocardial infarct size and apoptosis were markedly reduced, and contractile function was significantly improved in the TAC preconditioning group compared with the control group. Mechanistically, hypertrophic preconditioning remarkably alleviated I/R-induced oxidative stress, as evidenced by the increased reduced nicotinamide adenine dinucleotide phosphate (NADPH)/nicotinamide adenine dinucleotide phosphate (NADP) ratio, increase in the reduced glutathione (GSH)/oxidized glutathione (GSSH) ratio, and reduced mitochondrial reactive oxygen species (ROS) production. Moreover, TAC preconditioning inhibited caspase-3 activation and mitigated the mitochondrial impairment by deacetylating isocitrate dehydrogenase 2 (IDH2) via a sirtuin 3 (SIRT3)-dependent mechanism. In addition, the expression of a genetic deacetylation mimetic IDH2 mutant (IDH2 K413R) in cardiomyocytes, which increased IDH2 enzymatic activity and decreased mitochondrial ROS production, and ameliorated I/R injury, whereas the expression of a genetic acetylation mimetic (IDH2 K413Q) in cardiomyocytes abolished these protective effects of hypertrophic preconditioning. Furthermore, both the activity and expression of the SIRT3 protein were markedly increased in preconditioned mice exposed to I/R. Treatment with an adenovirus encoding SIRT3 partially emulated the actions of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. The present study identifies hypertrophic preconditioning as a novel endogenous self-defensive and cardioprotective strategy for cardiac I/R injury that induces IDH2 deacetylation through a SIRT3-dependent mechanism. A therapeutic strategy targeting IDH2 may be a promising treatment for cardiac ischemic injury.
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