Trimetazidine protects against myocardial ischemia/reperfusion injury by inhibiting excessive autophagy
Trimetazidine protects against myocardial ischemia/reperfusion injury by inhibiting excessive autophagy
复制标题
曲美他嗪抑制过度自噬对心肌缺血再灌注损伤的保护作用
DOI：
10.1007/s00109-018-1664-3
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发表时间：
2018-08-01
影响因子：
4.7
通讯作者：
Zhang, Dongying
中科院分区：
文献类型：
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作者：
Wu, Shiyong;Chang, Guanglei;Zhang, Dongying
曲美他嗪（TMZ）已被证明对心肌缺血/再灌注（MI/R）损伤具有保护作用。在本研究中，我们研究了TMZ在体内和体外对MI/R期间自噬的影响及其机制。在体内研究中，通过冠状动脉闭塞诱导MI/R的动物模型。TMZ（20 mg/kg/天）通过增加射血分数和缩短分数以及降低收缩末期容积、舒张末期容积、收缩期左心室（LV）内径和舒张末期LV内径，保护大鼠心脏免于MI/R诱导的心力衰竭;通过降低LDH、肌酸激酶MB同工酶、ROS，和MDA水平以及增加SOD和谷胱甘肽过氧化物酶水平。TMZ还减少心肌梗死面积和细胞凋亡。此外，TMZ通过降低LC 3-II、Beclin 1、ATG 5和ATG 7的蛋白和信使RNA水平以及自噬体的数量，并通过涉及AKT/mTOR通路，显著抑制MI/R诱导的自噬。此外，在体外实验中，将H9 c2细胞与TMZ（40 μ M）一起孵育以探索TMZ在暴露于缺氧和再氧合（H/R）后的直接作用。TMZ可增加细胞活力和细胞内SOD的浓度，抑制H/R诱导的细胞凋亡和ROS的产生。此外，TMZ减少了自噬体的数量和自噬相关蛋白的表达;它还上调了p-AKT和p-mTOR的表达。TMZ还可增加Bcl-2蛋白表达，降低Bax蛋白表达、Bax/Bcl-2比值和caspase-3裂解水平。然而，这些对H9 c2细胞的影响被PI 3 K抑制剂LY 294002显著地消除。总之，我们的结果表明TMZ抑制I/R诱导的过度自噬和凋亡，这至少部分是通过激活AKT/mTOR通路介导的。TMZ改善心功能，减轻心肌损伤和氧化应激，减少心肌梗死面积和凋亡。TMZ抑制MI/R诱导的心肌自噬，H/R诱导的H9 c2细胞凋亡，TMZ可通过激活AKT/mTOR通路抑制心肌细胞过度自噬，从而保护心肌细胞免受MI/R损伤。
Trimetazidine (TMZ) has been demonstrated to have protective effects against myocardial ischemia/reperfusion (MI/R) injury. In the present study, we investigated the effects and the underlying mechanisms of TMZ on autophagy during MI/R in vivo and in vitro. In the in vivo study, an animal model of MI/R was induced by coronary occlusion. TMZ (20 mg/kg/day) protected the rat hearts from MI/R-induced heart failure by increasing ejection fraction and fractional shortening and decreasing end-systolic volume, end-diastolic volume, left ventricular (LV) internal diameter at systole, and LV internal diameter at diastole; it alleviated myocardial injury and oxidative stress by decreasing LDH, creatine kinase MB isoenzyme, ROS, and MDA levels and increasing SOD and glutathione peroxidase levels in plasma. TMZ also reduced myocardial infarct size and apoptosis. Moreover, TMZ markedly inhibited MI/R-induced autophagy by decreasing the protein and messenger RNA levels of LC3-II, Beclin1, ATG5, and ATG7 and the number of autophagosomes and by involving the AKT/mTOR pathway. Further, in the in vitro experiments, H9c2 cells were incubated with TMZ (40 mu M) to explore the direct effects of TMZ following exposure to hypoxia and reoxygenation (H/R). TMZ increased cell viability and the concentration of intracellular SOD and inhibited H/R-induced cell apoptosis and ROS production. Moreover, TMZ decreased the number of autophagosomes and autophagy-related protein expression; it also upregulated p-AKT and p-mTOR expression. In addition, TMZ augmented Bcl-2 protein expression and diminished Bax protein expression, the Bax/Bcl-2 rate, and cleaved caspase-3 level. However, these effects on H9c2 cells were notably abolished by the PI3K inhibitor LY294002. In conclusion, our results showed that TMZ inhibited I/R-induced excessive autophagy and apoptosis, which was, at least partly, mediated by activating the AKT/mTOR pathway.TMZ improved cardiac function, alleviated myocardial injury and oxidative stress, and reduced the myocardial infarct area and apoptosis.TMZ inhibited MI/R-induced myocardial autophagy, H/R-induced H9c2 cell apoptosis, and autophagy flux.The effect of TMZ on autophagy was repressed by LY294002.TMZ protected against MI/R injury by inhibiting excessive autophagy via activating the AKT/mTOR pathway.