Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity
Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity
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DOI：
10.1016/j.yjmcc.2009.07.024
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发表时间：
2009-11-01
影响因子：
5
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Yoshida, Masashi;Shiojima, Ichiro;Komuro, Issei
阿霉素具有累积的剂量依赖性心脏毒性，肿瘤抑制蛋白P53参与了阿霉素心脏毒性的发病机制。然而，P53是如何被阿霉素诱导并介导阿霉素的心脏毒性效应的，目前仍不清楚。在培养的心肌细胞中，阿霉素诱导氧化应激、DNA损伤、ATM激活和P53诱导。自由基清除剂NAC可减弱所有这些事件，而ATM激酶抑制剂Wortmannin可减弱阿霉素诱导的ATM激活和P53诱导，但不能减轻氧化应激。体内阿霉素治疗也会导致氧化应激、DNA损伤、ATM激活和P53积聚。这些观察结果表明，阿霉素诱导的P53是通过DNA氧化损伤-ATM途径介导的。在杂合子p53缺陷小鼠和心脏受限的Bcl2转基因小鼠体内，阿霉素引起的收缩功能障碍和心肌细胞凋亡均被减轻，提示心肌细胞凋亡在阿霉素心脏毒性中起着P53下游的核心作用。我们还检测了匹伐他汀是否对阿霉素心脏毒性有保护作用，减轻阿霉素引起的氧化应激、DNA损伤。ATM激活、P53积聚和体外细胞凋亡。在体内，匹伐他汀还可以减轻心肌细胞的凋亡和收缩功能障碍。甲伐他汀的有益作用被甲氧戊酸途径的中间产物逆转，而甲氧戊酸途径的中间产物是激活rac1所必需的，而rac1抑制剂显示出与匹伐他汀相当的心脏保护作用。这些数据表明阿霉素的心脏毒性是通过DNA氧化损伤-ATM-P53-细胞凋亡途径来介导的，而匹伐他汀通过其抗氧化作用而减轻这种毒性，其中包括对rac1的抑制。(C)2009 Elsevier Inc.保留所有权利。
Doxorubicin is known to have cumulative dose-dependent cardiotoxicity, and a tumor suppressor protein p53 has been implicated in the pathogenesis of doxorubicin cardiotoxicity. However, how p53 is induced by doxorubicin and mediates the cardiotoxic effects of doxorubicin remains elusive. In cultured cardiac myocytes, doxorubicin induced oxidative stress, DNA damage, ATM activation, and p53 induction. A free radical scavenger NAC attenuated all of these events, whereas an ATM kinase inhibitor wortmannin attenuated doxorubicin-induced ATM activation and p53 induction but not oxidative stress. Doxorubicin treatment in vivo also induced oxidative stress, DNA damage, ATM activation, and p53 accumulation. These observations suggest that p53 induction by doxorubicin is mediated by oxidative DNA damage-ATM pathway. Doxorubicin-induced contractile dysfunction and myocyte apoptosis in vivo were attenuated in heterozygous p53 deficient mice and cardiac-restricted Bcl-2 transgenic mice, suggesting that myocyte apoptosis plays a central role downstream of p53 in doxorubicin cardiotoxicity. We also tested whether pitavastatin exerts protective effects on doxorubicin cardiotoxicity Pitavastatin attenuated doxorubicin-induced oxidative stress, DNA damage. ATM activation, p53 accumulation, and apoptosis in vitro. Pitavastatin also attenuated myocyte apoptosis and contractile dysfunction in vivo. The beneficial effects of pitavastatin were reversed by intermediate products of the mevalonate pathway that are required for the activation of Rac1, and Rac1 inhibitor exhibited cardioprotective effects comparable to those of pitavastatin. These data collectively suggest that doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition. (C) 2009 Elsevier Inc. All rights reserved.