Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transigenic mice
Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transigenic mice
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DOI：
10.1016/s0002-9440(10)63514-6
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发表时间：
2003-10-01
影响因子：
6
通讯作者：
Sun, XH
中科院分区：
文献类型：
--
作者：
Kang, YJ;Li, Y;Sun, XH
先前的研究使用心脏特异性金属硫蛋白（MT）过表达转基因小鼠模型已经证明，MT抑制缺血/再灌注诱导的心肌损伤。本研究旨在验证MT抑制与线粒体细胞色素C释放和caspase-3激活介导的细胞凋亡抑制相关的假设。在MT过表达转基因小鼠和非转基因对照小鼠中使用开胸冠状动脉闭塞和再灌注程序来产生缺血/再灌注诱导的左心室梗死。缺血30分钟后，对左心室进行再灌注，使血液流过先前闭塞的冠状动脉床。MT转基因小鼠再灌注4小时后产生的心肌梗死显著减少。这种抑制与MT的抗凋亡作用相关，如通过末端脱氧核苷酸转移酶介导的脱氧尿苷5-三磷酸缺口末端标记试验、线粒体细胞色素c释放和caspase-3激活所确定的。缺血/再灌注诱导的脂质过氧化反应也显着抑制在MT转基因心脏。二甲亚砜，一种活性氧的化学清除剂，被用来证实MT的抗氧化作用，并发现抑制心肌梗死和脂质过氧化，就像MT一样。因此，本研究表明，MT抑制缺血/再灌注诱导的心肌细胞凋亡，至少部分，通过抑制细胞色素c介导的caspase-3激活途径。MT的抗凋亡作用可能是通过抑制氧化应激而实现的，并与抑制心肌梗死有关。
Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic mouse model have demonstrated that MT inhibits ischemia/reperfusion-induced myocardial injury. The present study was undertaken to test the hypothesis that the MT inhibition is associated with suppression of apoptosis mediated by mitochondrial cytochrome c release and caspase-3 activation. An open-chest coronary artery occlusion and reperfusion procedure to produce ischemia/reperfusion-induced left ventricle infarction was used in MT-overexpressing transgenic mice and non-transgenic controls. After 30 minutes of ischemia, the left ventricle was reperfused to allow blood flow through the previously occluded coronary artery bed. Myocardial infarction produced after reperfusion for 4 hours was significantly reduced in the MT transgenic mice. This inhibition correlated with the antiapoptotic effect of MT, as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling assay, mitochondrial cytochrome c release and caspase-3 activation. Ischemia/reperfusion-induced lipid peroxidation was also significantly inhibited in the MT-transgenic heart. Dimethylsulfoxide, a chemical scavenger for reactive oxygen species, was used to confirm the antioxidant effect of MT and found to suppress myocardial infarction and lipid peroxidation just as MT did. This study thus demonstrates that MT suppresses ischemia/reperfusion-induced myocardial apoptosis through, at least in part, the inhibition of cytochrome c-mediated caspase-3 activation pathway. The antiapoptotic effect of MT likely results from the suppression of oxidative stress and correlates with the inhibition of myocardial infarction.