Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion
Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion
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DOI：
10.1161/01.res.86.5.541
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发表时间：
2000-03-17
影响因子：
20.1
通讯作者：
Schumacker, PT
中科院分区：
文献类型：
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作者：
Vanden Hoek, TL;Becker, LB;Schumacker, PT
缺血/再灌注后心肌细胞死亡与氧化应激相关，抗氧化剂在该模型中具有保护作用。缺氧或腺苷预处理（PC）也可以提供保护，这使我们假设PC通过在随后的缺血/再灌注中减少氧化剂的产生来保护。用100 μ mol/L的腺苷或缺氧预处理10分钟，模拟缺血1小时，再灌注3小时。腺苷PC将细胞死亡率从50+/-3%降低到18+/-4%，并增强再灌注时的收缩恢复，正如之前在缺氧PC中观察到的那样。二氯荧光素（对H2O2敏感）氧化的短暂爆发在再灌注时被缺氧或腺苷引起的PC显著减弱。蛋白激酶C （PKC）抑制剂Go-6976和线粒体atp敏感的K+ (K- atp)通道抑制剂5-羟decanoate均可消除pc诱导的再灌注氧化应激衰减。相比之下，仅在再灌注时给予K+通道开启剂pinacidil或抗氧化剂2-巯基丙酰甘氨酸和1,10-菲罗啉可降低再灌注时的氧化应激，并改善生存和收缩恢复。因此，PC保护与再灌注时氧化剂爆发的衰减有关，而与触发PC的方法无关。与PKC抑制或K-ATP通道抑制剂相关的PC保护丧失与氧化应激的恢复有关。这些结果提示了一种保护PC的机制，并揭示了PKC激活和K-ATP通道激活之间的功能联系。
Cardiomyocyte death after ischemia/reperfusion correlates with oxidant stress, and antioxidants confer protection in that model. Preconditioning (PC) with hypoxia or adenosine also confers protection, leading us to hypothesize that PC protects by attenuating oxidant generation during subsequent ischemia/reperfusion. Chick cardiomyocytes were preconditioned with 10 minutes of hypoxia or adenosine (100 mu mol/L), followed by 1 hour of simulated ischemia and 3 hours of reperfusion. Adenosine PC decreased cell death from 50+/-3% to 18+/-4% and enhanced the return of contractions during reperfusion, as observed previously with hypoxic PC. A transient burst of dichlorofluorescein (sensitive to H2O2) oxidation that was significantly attenuated by PC initiated by hypoxia or adenosine was seen at reperfusion. The protein kinase C (PKC) inhibitor Go-6976 and the mitochondrial ATP-sensitive K+ (K-ATP) channel inhibitor 5-hydroxydecanoate each abolished protection and abrogated the PC-induced attenuation of reperfusion oxidant stress. By contrast, when given only at reperfusion, the K+ channel opener pinacidil or the antioxidants 2-mercaptopropionylglycine and 1,10-phenanthroline decreased oxidant stress at reperfusion and improved survival and return of contractions. Thus, PC protection is associated with an attenuation of the oxidant burst at reperfusion, regardless of the method by which PC is triggered. Loss of PC protection associated with PKC inhibition or K-ATP, channel inhibitors is associated with a restoration of that oxidant stress. These results suggest a mechanism for PC protection and reveal a functional link between PKC activation and K-ATP channel activation in that pathway.