Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity
Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity
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DOI：
10.1161/01.cir.0000027817.55925.b4
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发表时间：
2002-09-10
期刊：
影响因子：
37.8
通讯作者：
Yodoi, J
中科院分区：
文献类型：
--
作者：
Shioji, K;Kishimoto, C;Yodoi, J
背景-阿霉素(ADR)是一种已知的抗癌药物，通过产生自由基而导致严重的心脏毒性。我们研究了氧化还原调节分子硫氧还蛋白-1(TRX1)在ADR诱导的心脏毒性中的作用。方法与结果-体外研究表明，在ADR处理的新生大鼠心肌细胞中，TRX1呈剂量依赖性增加，伴随着羟基自由基的形成。乳酸脱氢酶释放实验显示，重组人TRX1可抑制ADR处理的心肌细胞损伤。为了检验TRX1在体内的生物学意义，我们使用了表达人TRX1水平增加的转基因小鼠(TRX1-TG小鼠)。电子显微镜显示，与ADR处理的非转基因(WT)小鼠相比，接受ADR处理的TRX1-TG小鼠的线粒体、肌原纤维和其他细胞细节保持得更好。ADR处理的TRX1-TG小鼠与ADR处理的WT小鼠相比，其细胞蛋白质氧化的标志--蛋白质羰基含量的增加受到抑制。与WT小鼠相比，经ADR处理的TRX1-TG小鼠心脏匀浆中羟基自由基的生成减少。在生存研究中，所有接受ADR治疗的WT小鼠在6周内死亡，但6只接受ADR治疗的TRX1-TG小鼠中有5只存活8周。结论-TRX1是由ADR产生的细胞内氧化应激上调的。TRX1通过减少氧化应激，对ADR所致的心脏毒性具有保护作用。
Background-Adriamycin (ADR) is an anticancer drug known to cause severe cardiac toxicity by generating free radicals. We investigated the role of a redox-regulating molecule, thioredoxin-1 (TRX1), in ADR-induced cardiotoxicity.Methods and Results-The in vitro study showed that TRX1 was dose-dependently increased concomitant with the formation of hydroxyl radicals in ADR-treated neonatal rat cardiomyocytes. Lactate dehydrogenase-releasing assay showed that treatment with recombinant human TRX1 suppressed cardiomyocyte injury in ADR-treated cardiomyocytes. To examine the biological significance of TRX1 in vivo, we used transgenic mice expressing increased levels of human TRX1 (TRX1-TG mice). Electron microscopy revealed that mitochondria, myofibrils, and other cellular details were much better maintained in ADR-treated TRX1-TG mice than in ADR-treated nontransgenic (WT) mice. The increase in the protein carbonyl content, a marker of cellular protein oxidation, was suppressed in ADR-treated TRX1-TG mice compared with ADR-treated WT mice. The formation of hydroxyl radicals in ADR-treated heart homogenates of TRX1-TG mice was decreased compared with WT mice. For the survival study, all WT mice treated with ADR died within 6 weeks, but 5 of 6 TRX1-TG mice treated with ADR survived >8 weeks.Conclusions-TRX1 is upregulated by intracellular oxidative stress generated by ADR. TRX1 has a protective role against ADR-induced cardiotoxicity by reducing oxidative stress.