Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression
Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression
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DOI：
10.1152/ajpheart.00143.2003
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发表时间：
2003-11-01
影响因子：
4.8
通讯作者：
Maeda, H
中科院分区：
文献类型：
--
作者：
Rajesh, KG;Sasaguri, S;Maeda, H
缺血一段时间后的再灌注与活性氧（ROS）和Ca 2+过载的形成相关，导致线粒体内膜中的非特异性孔（称为线粒体通透性转换孔（PTP））打开，导致细胞损伤。虽然内源性抗氧化剂由于缺血后的氧化应激而被激活，但它们的水平不足以防止再灌注损伤。因此，总是需要外源性补充抗氧化剂，特别是在急性缺血后。在这里，我们证明了抗氧化剂3-甲基-1-苯基-2-吡唑啉-5-酮（MCI-186）通过抑制PTP开放来预防心脏再灌注损伤的作用。在用MCI-186预处理后，在Wistar大鼠中通过左冠状动脉（LCA）闭塞和再灌注（20分钟）的缺血（30分钟在左冠状动脉闭塞前30 min开始静脉输注（10 mg/kg）导致1）心肌梗死面积减少（19.2% vs. 61.6%），2）心肌ATP含量维持良好（与对照组相比P < 0.03），3）减少线粒体肿胀和减少细胞色素c释放，4）增加BCl-2的表达，5）凋亡细胞的发生率较低（14.3%对2.9%），和6）MCI-186处理组中DNA片段化减少。MCI-186的这些细胞保护作用在用PTP激活剂氯尼达明（lonidamine）（10 mg/kg iv）或甘草苷（5 mg/kg iv）处理MCI-186之前在打开PTP时被抑制，但未能抑制由另一种抗氧化剂别嘌呤醇施加的保护作用，这表明PTP抑制特性对MCI-186是特异性的。这些结果表明，自由基清除剂MCI-186通过抑制PTP的开放，防止坏死和细胞色素c释放，从而防止病理性细胞凋亡。
Reperfusion after a period of ischemia is associated with the formation of reactive oxygen species (ROS) and Ca2+ overload resulting in the opening of a nonspecific pore in the inner membrane of the mitochondria, called the mitochondrial permeability transition pore (PTP), leading to cell damage. Although endogenous antioxidants are activated because of oxidative stress following ischemia, their levels are not high enough to prevent reperfusion injury. Hence there is always a need for exogenous supplement of antioxidants, especially after acute ischemia. Here we demonstrated the effects of the antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) in preventing reperfusion injury of the heart by inhibition of PTP opening. Ischemia (30 min) by left coronary artery (LCA) occlusion and reperfusion ( 20 min) in Wistar rats after pretreatment with MCI-186 (10 mg/kg iv) infusion starting from 30 min before LCA occlusion resulted in 1) less area of myocardial infarction (19.2% vs. 61.6%), 2) well-maintained myocardial ATP content (P < 0.03 vs. control), 3) decreased mitochondrial swelling and reduced cytochrome c release, 4) increased expression of BCl-2, 5) lower prevalence of apoptotic cells (14.3% vs. 2.9%), and 6) reduced DNA fragmentation in the MCI-186-treated group. These cytoprotective effects of MCI-186 were inhibited on opening PTP before MCI-186 treatment with the PTP activators lonidamine (10 mg/kg iv) or atractyloside (5 mg/kg iv) but failed to inhibit the protective effects exerted by another antioxidant, allopurinol, suggesting that the PTP inhibiting property is specific for MCI-186. These results demonstrate that the radical scavenger MCI-186, by inhibiting the opening of the PTP, prevents necrosis and cytochrome c release and hence pathological apoptosis.