Manganese superoxide dismutase and inducible nitric oxide synthase modify early oxidative events in acute Adriamycin-induced mitochondrial toxicity
Manganese superoxide dismutase and inducible nitric oxide synthase modify early oxidative events in acute Adriamycin-induced mitochondrial toxicity
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DOI：
10.1158/1535-7163.mct-04-0322
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发表时间：
2005-07-01
影响因子：
5.7
通讯作者：
Oberley, TD
中科院分区：
文献类型：
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作者：
Chaiswing, L;Cole, MP;Oberley, TD
在本研究中，我们利用基因工程B6C3小鼠[高表达超氧化物歧化酶(TGM(+/+))、诱导型一氧化氮合酶失活(iNOSKO(-/-))及其杂交]来研究锰超氧化物歧化酶(MnSOD)和诱导型一氧化氮合酶(INOS)在阿霉素急性心脏毒性中的作用。非转基因小鼠和转基因小鼠在0、3、6和24小时分别接受20 mg/kg阿霉素和心脏左心室组织的治疗。采用免疫金超微技术检测心肌细胞超微结构损伤及4-羟基-2-壬烯醛(4HNE)蛋白加合物和3-硝基酪氨酸(3NT)水平。我们先前的结果表明，阿霉素在早期时间点引起线粒体损伤，但没有明显的核或细胞质损伤。有趣的是，与非转基因小鼠心肌细胞线粒体的损伤水平相比，MnSOD的过表达对急性线粒体损伤具有保护作用，而NOS缺乏则加剧了线粒体损伤。在TGM(+/+)小鼠中，线粒体损伤与各时间点的4HNE/3NT水平呈显著负相关，提示活性氧/活性氮损伤产物直接调节阿霉素所致的急性线粒体损伤。本研究首次直接量化了在阿霉素诱导的急性心脏毒性过程中MnSOD和NOS对线粒体损伤的影响，并显示了阿霉素治疗后线粒体蛋白质翻译后修饰的广泛和特定的模式。
In the present study, we used genetically engineered B6C3 mice [mice overexpressing manganese superoxide dismutase (TgM(+/+)), mice in which inducible nitric oxide synthase had been inactivated (iNOSKO(-/-)), and crosses of these two genotypes] to study the role of manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS) in the development of acute Adriamycin-induced cardiotoxicity. Both nontransgenic and genetically engineered mice were treated with 20 mg/kg Adriamycin and cardiac left ventricular tissues studied at 0, 3, 6, and 24 hours. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE) protein adducts and 3-nitrotyrosine (3NT) were determined in cardiomyocytes using immunogold ultrastructural techniques. Our previous results showed that Adriamycin caused mitochondrial injury without significant nuclear or cytoplasmic damage at early time points. Interestingly, overexpression of MnSOD protected against acute mitochondrial injury, whereas deficiency in NOS potentiated mitochondrial injury in comparison with levels of injury present in cardiomyocyte mitochondria of nontransgenic mice. In TgM(+/+) mice, there was a significant inverse correlation between mitochondrial injury and 4HNE/3NT levels at all time points analyzed, suggesting that reactive oxygen species/reactive nitrogen species damage products directly regulated acute Adriamycin-induced mitochondrial injury in these mice. The present studies are the first to directly quantify the effects of MnSOD and NOS on mitochondrial injury during acute Adriamycin-induced cardiotoxicity and show extensive and specific patterns of posttranslational modifications of mitochondrial proteins following Adriamycin treatment.