AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis
AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis
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DOI：
10.1016/j.freeradbiomed.2018.08.032
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发表时间：
2018-12-01
影响因子：
7.4
通讯作者：
Yuan, Jiansong
中科院分区：
文献类型：
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作者：
Liu, Dong;Ma, Zhiqiang;Yuan, Jiansong
多柔比星（DOX）是一种高效的蒽环类抗癌药物，但其在心脏水平的副作用限制了其广泛的临床应用。褪黑激素是一种有效的抗氧化剂，无毒和心脏保护剂，它参与维持线粒体稳态和功能。本研究在用1 μ M DOX孵育的H9 c2细胞和用DOX（20 mg/kg累积剂量）处理的C57 BL/6小鼠中建立了急性DOX诱导的心脏毒性模型。褪黑素可明显减轻DOX所致的急性心功能不全和心肌损伤。体内和体外研究均证实，褪黑激素通过激活AMPK和上调PGC 1 α及其下游信号（NRF 1、TFAM和UCP 2）抑制DOX诱导的线粒体功能障碍和形态学障碍、细胞凋亡和氧化应激。这些作用通过在H9 c2细胞中使用AMPK siRNA或PGC 1 α siRNA而逆转，并且也通过与AMPK抑制剂化合物C在体内共处理而被否定。此外，PGC 1 α敲低对DOX处理的H9 c2细胞中褪黑激素诱导的AMPK磷酸化没有影响。因此，AMPK/PGC 1 α通路激活可能代表褪黑激素通过保护线粒体稳态和减轻氧化应激和细胞凋亡而对急性DOX心脏毒性产生保护作用的新机制。
Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 mu M DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1 alpha with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1 alpha siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1 alpha knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1 alpha pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.