Suppression of Ischemia-Reperfusion Myocardial Damage via Enhancement of Repair of Oxidative DNA Damage

离体兔心缺血/再灌注30/60 min后，5/10 min预处理可明显缩小心肌梗死面积，尤以内膜下心肌梗死明显。外源性H_2O_2可加重心肌缺血/再灌注损伤，尤其是心外膜下。还原型谷胱甘肽水平，但谷胱甘肽过氧化物酶的活动，以及保存transmartally在预处理的心脏。对照组血清DNA氧化损伤指标8-OHdG水平升高，以心内膜下明显，H_2O_2负荷再灌注时明显升高，以心外膜下明显（p<0.01）。这些变化被预处理有效地减少。免疫组化检测结果显示，心肌梗死边缘区的核酸内切酶表达无明显变化，但蛋白质水平明显升高。口服依布硒林，谷胱甘肽过氧化物酶样抗氧化剂发挥药理学预处理样作用。依布硒啉沿着还原型谷胱甘肽的保护和心肌8-脱氧鸟苷酶水平的类似降低，可显著抑制H_2O_2对心肌的损伤作用。Ebselen显著增强热休克蛋白72（HSP 72）的表达。一种特异性HSP抑制剂，KNK 437在培养的心肌细胞中消除了依布硒啉的心脏保护作用，表明分子伴侣介导了依布硒啉的心脏保护作用。

The myocardial infarct size of isolated rabbit hearts undergone 30/60min of ischemia/reperfusion was significantly reduced in 5/10min preconditioned hearts, particularly in the subendocardium. Exogenous H_2O_2 aggravated ischemia/reperfusion injury, particularly in the subepicardium. The reduced form of glutathione levels, but not glutathione peroxidase activities were well preserved transmurally in preconditioned hearts. The serum levels of 8-hydroxydeoxyguanosine(8-OHdG), an indicator of oxidative DNA damage, were increased in ontrol, predominantly in the subendocardium, and it was significantly enhanced in H_2O_2 loading on reperfusion, particularly in the subepicardium(p<0.01). These changes were effectively diminished by preconditioning. The expression of endnuclease assessed by immuno-histochemistry was not significantly affected, but protein levels were detected to be increased at the border-zone of infarction by western blotting. Orally administered ebselene, a glutathione peroxidase like antioxidant exerted pharmacological preconditioning like effect. The enhancement of myocardial damage by H_2O_2 was significantly suppressed by ebselen along with preservation of glutathione and similar reduction in myocardial 8-deoxyguanosme levels. Ebselen markedly enhanced heat shock protein 72(HSP72) expression. A specific HSP inhibitor, KNK437 abolished cardio protective effects of ebselen in cultured myocytes suggesting molecular chaperon mediates cardioprotective effects of ebselen.