Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové, 500 38, Czech Republic.
J Pharmacol Exp Ther. 2012 Nov;343(2):468-78. doi: 10.1124/jpet.112.198358. Epub 2012 Aug 22.
Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage. In this study, molecular and functional changes induced by chronic anthracycline treatment with progression into HF in post-treatment follow-up were analyzed with special emphasis on nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathways. Chronic cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg, weekly for 10 weeks), and the animals were followed for another 10 weeks. Echocardiography revealed a significant drop in left ventricular (LV) systolic function during the treatment with marked progression to LV dilation and congestive HF in the follow-up. Although daunorubicin-induced LV lipoperoxidation was found, it was only loosely associated with cardiac performance. Furthermore, although LV oxidized glutathione content was increased, the oxidized-to-reduced glutathione ratio itself remained unchanged. Neither Nrf2, the master regulator of antioxidant response, nor the majority of its target genes showed up-regulation in the study. However, down-regulation of manganese superoxide dismutase and NAD(P)H dehydrogenase [quinone] 1 were observed together with heme oxygenase 1 up-regulation. Although marked perturbations in mitochondrial functions were found, no induction of PGC1α-controlled mitochondrial biogenesis pathway was revealed. Instead, especially in the post-treatment period, an impaired regulation of this pathway was observed along with down-regulation of the expression of mitochondrial genes. These results imply that global oxidative stress need not be a factor responsible for the development of anthracycline-induced HF, whereas suppression of mitochondrial biogenesis might be involved.
蒽环类抗癌药物（如多柔比星或柔红霉素）可引起慢性心脏毒性和心力衰竭（HF），这两者都被认为是基于氧化损伤和线粒体损伤。在这项研究中，分析了慢性蒽环类药物治疗后进展为 HF 的后续治疗中引起的分子和功能变化，特别强调核因子红细胞 2 相关因子 2（Nrf2）和过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC1α）途径。用柔红霉素（3mg/kg，每周 1 次，共 10 周）诱导兔慢性心脏毒性，并对动物进行了另外 10 周的随访。超声心动图显示左心室（LV）收缩功能在治疗期间明显下降，随后 LV 扩张和充血性 HF 明显进展。尽管发现柔红霉素诱导的 LV 脂质过氧化，但与心脏功能仅有松散的关联。此外，尽管 LV 氧化型谷胱甘肽含量增加，但氧化型/还原型谷胱甘肽比值本身保持不变。Nrf2 是抗氧化反应的主要调节剂，其大多数靶基因在研究中均未上调。然而，观察到锰超氧化物歧化酶和 NAD（P）H 脱氢酶[醌]1 的下调，同时血红素加氧酶 1 的上调。尽管发现线粒体功能明显受到干扰，但未揭示 PGC1α 控制的线粒体生物发生途径的诱导。相反，尤其是在治疗后期间，观察到该途径的调节受损，同时线粒体基因的表达下调。这些结果表明，全身性氧化应激不一定是导致蒽环类药物诱导的 HF 发展的因素，而抑制线粒体生物发生可能与此有关。
