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resistant to subsequent ischemic stress,short-term transverse aortic constriction(TAC)was performed in mice and then withdrawn for several days by aortic debanding,followed by subsequent myocardial exposure to ischemia/reperfusion(I/R).Following I/R injury,the myocardial infarct size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 therapeu
为了验证撤除短期的压力超负荷可以使心脏抵抗随后的缺血性损伤,本研究采用在体结扎小鼠冠状动脉的方法制备心肌缺血再灌注损伤模型.采用动脉缩窄的方法诱导短期的压力超负荷以探讨肥厚预适应对心脏缺血再灌注损伤的影响.移除短期的压力超负荷(主动脉缩窄3天随后去缩窄4天)可以显著降低小鼠的心肌梗死面积,减轻心肌细胞凋亡并改善心脏收缩功能.肥厚预适应显著降低缺血再灌注损伤诱导的氧化应激,具体表现为增加NADPH/NADP和GSH/GSSH的比率,降低线粒体活性氧成分的产生.肥厚预适应通过去乙酰化酶3依赖的机制降低异柠檬酸脱氢酶2乙酰化,抑制caspase 3活化并减轻线粒体损伤.在小鼠体内转染异柠檬酸脱氢酶2去乙酰化的突变体(IDH2K413R)显著降低线粒体活性氧成分的产生并抑制心肌缺血再灌注损伤,而在小鼠体内过表达异柠檬酸脱氢酶2乙酰化的突变体(IDH2K413Q)取消了肥厚预适应的心肌保护效应.肥厚预适应显著促进去乙酰化酶3蛋白的活化,在小鼠体内过表达去乙酰化酶3蛋白可以部分模拟肥厚预适应的心肌保护作用,而敲除去乙酰化酶3蛋白取消了肥厚预适应的心肌保护作用.该研究表明肥厚预适是一种全新的内源性的心肌保护措施,其通过去乙酰化酶3依赖的机制诱导异柠檬酸脱氢酶2去乙酰化而发挥心肌保护效应.异柠檬酸脱氢酶2可能是一个潜在的治疗缺血性心肌损伤的新靶点.
作者
Leilei Ma
Hongtao Shi
Yang Li
Wei Gao
Junjie Guo
Jianbing Zhu
Zheng Dong
Aijun Sun
Yunzeng Zou
Junbo Ge
马雷雷;石洪涛;李洋;高微;郭俊杰;朱建兵;董正;孙爱军;邹云增;葛均波(Department of Cardiology,Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital,Fudan University,Shanghai 200032,China;NHC Key Laboratory of Viral Heart Diseases,Shanghai 200032,China;Key Laboratory of Viral Heart Diseases,Chinese Academy of Medical Sciences,Shanghai 200032,China;Institute of Biomedical Science,Fudan University,Shanghai 200032,China;Department of Cardiology,The Affiliated Hospital of Qingdao University,Qingdao 266101,China;Qingdao Municipal Key Laboratory of Hypertension(Key Laboratory of Cardiovascular Medicine),Qingdao 266101,China;Department of Cardiology,The First Affiliated Hospital of Nanchang University,Nanchang 330006,China;Jiangxi Hypertension Research Institute,Nanchang 330006,China)
基金
supported by the National Natural Science Foundation of China(81870290,81521001,81800235,and 81800238)。
