Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction.
Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction.
复制标题
Nrf2 缺乏会加剧阿霉素引起的心脏毒性和心脏功能障碍
DOI：
10.1155/2014/748524
复制
发表时间：
2014
影响因子：
--
通讯作者：
Cui T
中科院分区：
文献类型：
--
作者：
Li S;Wang W;Niu T;Wang H;Li B;Shao L;Lai Y;Li H;Janicki JS;Wang XL;Tang D;Cui T
多柔比星（Dox）的急性和慢性心脏毒性限制了其抗肿瘤治疗。除了氧化应激的致病作用外，自噬似乎在调节Dox诱导的心脏毒性中起重要作用。然而，其潜在机制仍不清楚。因此，我们探讨了核因子红细胞-2相关因子2（Nrf 2）在Dox诱导的心肌病中的作用，重点是心肌氧化应激和自噬活性。在野生型（WT）小鼠中，单次腹腔注射25 mg/kg Dox迅速诱导心肌细胞坏死和心功能障碍，这与氧化应激、自噬受损和聚泛素化蛋白聚集体积累有关。然而，这些Dox诱导的不良反应在Nrf 2敲除（Nrf 2 −/−）小鼠中被夸大了。在培养的心肌细胞中，Nrf 2的过表达增加了LC 3-II的稳定水平，改善了Dox诱导的自噬通量和泛素化蛋白聚集体的积累的损害，并抑制了Dox诱导的细胞毒性，而Nrf 2的敲低产生相反的效果。此外，通过过表达自噬相关基因5（Atg 5）强制激活自噬，大大减弱了Dox中毒的Nrf 2耗竭心肌细胞中夸大的不良反应。因此，这些结果表明，Nrf 2可能是通过控制心脏中的氧化应激和自噬来抑制Dox诱导的心脏毒性的内源性抑制剂。
The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
登录
查看更多内容
影响因子：
37.8
作者：
Calvert JW;Elston M;Nicholson CK;Gundewar S;Jha S;Elrod JW;Ramachandran A;Lefer DJ
通讯作者：
Lefer DJ
影响因子：
3.6
作者：
Dimitrakis, Polychronis;Romay-Ogando, Maria-Iris;Zuppinger, Christian
通讯作者：
Zuppinger, Christian
影响因子：
4.8
作者：
Petiot, A;Ogier-Denis, E;Codogno, P
通讯作者：
Codogno, P
影响因子：
2.9
作者：
Miller, Douglas L.;Li, Peng;Gordon, David
通讯作者：
Gordon, David
影响因子：
4.8
作者：
Kobayashi, Satoru;Volden, Paul;Liang, Qiangrong
通讯作者：
Liang, Qiangrong