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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation.
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Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation.

机译：硫氧还蛋白在心肌缺血中的心脏保护作用和S-亚硝化的再灌注作用。

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摘要

Apoptosis contributes to myocardial ischemia/reperfusion (MI/R) injury, and both thioredoxin (Trx) and nitric oxide have been shown to exert antiapoptotic effects in vitro. Recent evidence suggests that this particular action of Trx requires S-nitrosation at Cys-69. The present study sought to investigate whether or not exogenously applied Trx reduces MI/R injury in vivo and to which extent this effect depends on S-nitrosation. Adult mice were subjected to 30 min of MI and treated with either vehicle or human Trx (hTrx, 2 mg/kg, i.p.) 10 min before reperfusion. Native hTrx was incorporated into myocardial tissue as shown by immunostaining, and reduced MI/R injury as evidenced by decreased terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, DNA fragmentation, caspase-3 activity, and infarct size. When hTrx was partially S-nitrosated by preincubation with S-nitrosoglutathione, its cardioprotective effect was markedly enhanced. Treatment with hTrx significantly reduced p38 mitogen-activated protein kinase (MAPK) activity, and this effect was also potentiated by S-nitrosation. To further address the role of S-nitrosation for the overall antiapoptotic effect to Trx, the action of Escherichia coli Trx (eTrx) was investigated in the same model. Whereas eTrx inhibited MI/R-induced apoptosis to a degree similar to hTrx, S-nitrosation of this protein, which lacks Cys-69, failed to further enhance its antiapoptotic action. Collectively, our results demonstrate that systemically applied Trx is taken up by the myocardium to exert potent cardioprotective effects in vivo, offering interesting therapeutic avenues. In the case of hTrx, these effects are further potentiated by S-nitrosation, but this posttranslational modification is not essential for protection.
机译：凋亡导致心肌缺血/再灌注（MI / R）损伤，并且硫氧还蛋白（Trx）和一氧化氮均已显示出在体外发挥抗凋亡作用。最近的证据表明，Trx的这种特殊作用需要在Cys-69处进行S-亚硝化。本研究试图调查外源性Trx是否能减轻体内MI / R损伤，并且这种作用在多大程度上取决于S-亚硝化作用。成年小鼠经历30分钟的心梗，并在再灌注前10分钟用赋形剂或人Trx（hTrx，2 mg / kg，腹腔注射）治疗。如免疫染色所示，将天然hTrx掺入心肌组织，并通过减少末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色，DNA片段化，caspase-3活性和梗死面积来证明MI / R损伤减少。当通过与S-亚硝基谷胱甘肽预温育将hTrx部分S-亚硝化时，其心脏保护作用显着增强。 hTrx的治疗显着降低了p38丝裂原激活的蛋白激酶（MAPK）的活性，并且S-亚硝化作用也增强了这种作用。为了进一步解决S-亚硝化对Trx总体抗凋亡作用的作用，在同一模型中研究了大肠杆菌Trx（eTrx）的作用。尽管eTrx抑制MI / R诱导的细胞凋亡的程度与hTrx相似，但缺少Cys-69的该蛋白的S-亚硝化不能进一步增强其抗凋亡作用。总体而言，我们的结果表明，全身应用的Trx被心肌吸收，在体内发挥有效的心脏保护作用，从而提供了有趣的治疗途径。在hTrx的情况下，这些作用会通过S-亚硝化作用进一步增强，但是这种翻译后修饰对于保护并不是必需的。

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