Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury.
Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury.
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DOI：
10.1016/j.yjmcc.2004.12.001
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发表时间：
2005-02-01
影响因子：
5
通讯作者：
Ovize, Michel
中科院分区：
文献类型：
--
作者：
Argaud, Laurent;Gateau-Roesch, Odile;Ovize, Michel
本研究的目的是确定在急性心肌梗死后再灌注时，NIM 811特异性抑制线粒体通透性转换（MPT）是否可以保护心脏。MPT孔开放似乎是急性心肌梗死后细胞死亡的关键事件。近年来，MPT孔开放参与了缺血预适应。在方案1中，NZW兔经历无干预（假手术）或缺血10分钟，随后再灌注5分钟，在缺血5分钟和再灌注5分钟之前（预处理，PC）或不（对照，C）。在缺血前10分钟或再灌注前1分钟，用环孢菌素A（CsA）或其非免疫抑制性和更特异性的衍生物（NIM 811）（10 mg/kg，IV推注）治疗其他家兔。切除心脏并分离线粒体以进一步评估Ca（2+）诱导的MPT。在方案2中，动物被随机分配到类似的实验组，并经历30分钟的缺血和4小时的再灌注。TTC染色检测细胞大小，TUNEL法检测细胞凋亡。NIM 811、CsA和PC组诱导MPT孔开放所需的Ca ~（2+）超载显著高于对照组。NIM 811、CsA和PC均能显著降低心肌细胞坏死和凋亡。在两种方案中，在再灌注时施用NIM 811提供了完全保护。这些数据表明，在急性心肌梗死后再灌注时特异性抑制MPT孔开放提供了强有力的抗坏死和抗凋亡保护。
The aim of the present study was to determine whether specific inhibition of mitochondrial permeability transition (MPT) by NIM811 at the time of reperfusion following acute myocardial infarction may protect the heart. MPT pore opening appears to be a pivotal event in cell death following acute myocardial infarction. Recently, MPT pore opening has been involved in ischemic preconditioning. In protocol 1, NZW rabbits underwent either no intervention (sham) or 10 min of ischemia followed by 5 min of reperfusion, preceded (preconditioned, PC) or not (control, C) by 5 min of ischemia and 5 min of reperfusion. Additional rabbits were treated by cyclosporin A (CsA) or its non-immunosuppressive and more specific derivative (NIM811) (10 mg kg(-1), IV bolus), either 10 min before ischemia or 1 min before reperfusion. Hearts were excised and mitochondria isolated for further assessment of Ca(2+)-induced MPT. In protocol 2, animals were randomly assigned into similar experimental groups and underwent 30 min of ischemia and 4 h of reperfusion. Infarct size was assessed by TTC staining, and apoptosis by TUNEL assay. The Ca2+ overload required to induce MPT pore opening was significantly higher in NIM811, CsA and PC groups than in controls. Both necrotic and apoptotic cardiomyocyte death were significantly reduced by NIM811, CsA and PC. In both protocols, administration of NIM811 at reperfusion provided full protection. These data indicate that specific inhibition of MPT pore opening at reperfusion following acute myocardial infarction provides a powerful antinecrotic and antiapoptotic protection.