Metallothionein Protects the Heart Against Myocardial Infarction via the mTORC2/FoxO3a/Bim Pathway
Metallothionein Protects the Heart Against Myocardial Infarction via the mTORC2/FoxO3a/Bim Pathway
复制标题
金属硫蛋白通过 mTORC2/FoxO3a/Bim 通路保护心脏免受心肌梗塞
DOI：
10.1089/ars.2018.7597
复制
发表时间：
2019
影响因子：
6.6
通讯作者：
Cong Weitao
中科院分区：
文献类型：
--
作者：
Xue Mei;Joo Young A;Li Santie;Niu Chao;Chen Gen;Yi Xinchu;Liang Yangzhi;Chen Zhiwei;Shen Yingjie;Ye Weijian;Cai Lu;Wang Xu;Jin Litai;Cong Weitao
目的：心脏特异性金属硫蛋白(MT)的过表达已被证明对缺血性心脏病有益，但MT保护心肌梗死(MI)的具体机制尚不清楚。本研究探讨mTORC2/FOXO3a/Bim通路在MT的心脏保护作用中的作用。结果：结扎冠状动脉左前降支(LAD)可诱导野生型(FVB)小鼠和心脏特异性MT过表达转基因(MT-TG)小鼠心肌梗死。MT-TG组小鼠心肌梗死后心功能明显好于FVB组，心肌梗死面积和心肌细胞凋亡率明显低于FVB组。此外，MT-TG小鼠在LAD结扎后表现出比FVB小鼠更好的表型，表现出与MI后MT-TG小鼠相同的ROS水平。雷帕霉素复合体2机械靶点(MTORC2)的激活是MT抗心肌梗死的重要机制之一。此外，MT还可减轻心肌梗死后磷酸化FOXO3a的下调，抑制位于FOXO3a下游的凋亡相关基因Bim的表达，降低心肌梗死后的细胞凋亡水平。为了在体外模拟缺血损伤的FVB和MT-TG小鼠，对H9c2和MT高表达的H9c2(H9c2MT7)心肌细胞进行缺氧和葡萄糖剥夺，结果与体内的结果一致。创新与结论：MT对心肌梗死的保护作用并不完全依赖于其清除ROS的能力。相反，MT的过度表达主要是通过mTORC2-FOXO3a-Bim途径来保护心肌梗死。
Aims:Cardiac-specific overexpression of metallothionein (MT) has been shown to be beneficial in ischemic heart disease, but the detailed mechanisms through which MT protects against myocardial infarction (MI) remain unknown. This study assessed the involvement of the mTORC2/FoxO3a/Bim pathway in the cardioprotective effects of MT.Results:MI was induced in wild-type (FVB) mice and in cardiac-specific MT-overexpressing transgenic (MT-TG) mice by ligation of the left anterior descending (LAD) coronary artery. Cardiac function was better; infarct size and cardiomyocyte apoptosis were lower in MT-TG mice than in FVB mice after MI. Moreover, MT-TG mice exhibited better phenotypes after LAD ligation than FVB mice treated with Mn(III)tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; a reactive oxygen species [ROS] scavenger) and cardiac-specific catalase-overexpressing transgenic (CAT-TG) mice, which showed the same ROS levels as MT-TG mice after MI. Activation of mechanistic target of rapamycin complex 2 (mTORC2) was essential for the cardioprotective effects of MT against MI. In addition, MT attenuated the downregulation of phospho-FoxO3a after MI, inhibiting the expression of the apoptosis-associated geneBim, located downstream of FoxO3a, and reducing the level of apoptosis after MI. To mimic ischemic-injured FVB and MT-TG micein vitro, H9c2 and MT-overexpressing H9c2 (H9c2MT7) cardiomyocytes were subjected to oxygen and glucose deprivation, with the results being consistent with those obtainedin vivo.Innovation and Conclusion:The cardioprotective effects of MT against MI are not entirely dependent upon its ability to eliminate ROS. Rather, MT overexpression mostly protects against MI through the mTORC2-FoxO3a-Bim pathway.