The Radical Trap 5,5-Dimethyl-1-Pyrroline N-Oxide Exerts Dose-Dependent Protection against Myocardial Ischemia-Reperfusion Injury through Preservation of Mitochondrial Electron Transport
The Radical Trap 5,5-Dimethyl-1-Pyrroline N-Oxide Exerts Dose-Dependent Protection against Myocardial Ischemia-Reperfusion Injury through Preservation of Mitochondrial Electron Transport
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DOI：
10.1124/jpet.108.143479
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发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Zweier, Jay L.
中科院分区：
文献类型：
--
作者：
Zuo, Li;Chen, Yeong-Renn;Zweier, Jay L.
自由基是心肌缺血再灌注损伤的重要介质。硝酮自旋陷阱已被证明能抑制自由基。在离体心脏缺血再灌注模型上研究了自旋捕获剂5，5-二甲基-1-吡咯啉N-氧化物（DMPO）的心脏保护作用。对大鼠心脏进行灌注并使其经受全脑缺血30分钟，随后在诱导缺血之前用不同DMPO浓度（0.5-10 mM）的四个处理组进行再灌注。与未治疗的心脏相比，DMPO治疗改善了再灌注30分钟期间左心室（LV）功能和冠状动脉流量的恢复。在所有研究剂量下均观察到恢复增强，但在1 mM处理下恢复最高，LV发展压力恢复高2.4倍，梗死面积减少37%。超氧化物的测定采用组织荧光法，使用O（2）自由基阴离子探针氢乙定。用1 mM DMPO处理的心脏显示O（2）自由基阴离子显著减少。与对照心脏相比，在缺血的前5分钟内和在全缺血30分钟后再灌注时的产量。线粒体功能的研究表明，1 mM DMPO增加了再灌注30分钟后复合物I、II/III和IV的功能恢复。用针对复合物I、II和IV的抗体进行的免疫印迹进一步揭示了线粒体蛋白的显著上调，表明DMPO通过清除缺血/再灌注期间产生的氧自由基来防止其缺血性降解。因此，DMPO通过自由基清除作为针对缺血和缺血后损伤的保护剂发挥作用，通过挽救线粒体功能和氧化还原稳态赋予稳健的剂量依赖性保护。
Free radicals are important mediators of myocardial ischemia-reperfusion injury. Nitrone spin traps have been shown to scavenge free radicals. The cardioprotective effect of the spin trap, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), was investigated in an isolated heart model of global ischemia and reperfusion. Rat hearts were perfused and subjected to global ischemia for 30 min followed by reperfusion with four treatment groups of varying DMPO concentration (0.5-10 mM) administered before induction of ischemia. DMPO treatment improved the recovery of left ventricular (LV) function and coronary flow over the 30-min period of reperfusion compared with untreated hearts. Enhanced recovery was observed for all doses studied but was highest with 1 mM treatment with 2.4-fold higher recovery of LV developed pressure and 37% reduction in infarct size. Superoxide was measured by tissue fluorometry using the O(2)radical anion probe hydroethidine. Hearts treated with 1 mM DMPO showed a significant reduction in O(2)radical anion. production compared with control hearts both over the first 5 min of ischemia and upon reperfusion after 30 min of global ischemia. Studies of mitochondrial function demonstrated that 1 mM DMPO increased the recovery of function of complexes I, II/III, and IV after 30 min of reperfusion. Immunoblotting with antibodies against complexes I, II, and IV further revealed marked up-regulation of mitochondrial proteins, suggesting that DMPO prevents their ischemic degradation via scavenging oxygen radicals generated during ischemia/reperfusion. Thus, DMPO functions as a protective agent against ischemic and postischemic injury via radical scavenging, conferring robust dose-dependent protection with salvage of mitochondrial function and redox homeostasis.