Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction

被引:154
作者
Li, Siying [1 ,2 ]
Wang, Wenjuan [1 ,2 ]
Niu, Ting [1 ]
Wang, Hui [1 ,2 ]
Li, Bin [1 ,2 ]
Shao, Lei [1 ,2 ]
Lai, Yimu [2 ]
Li, Huanjie [1 ]
Janicki, Joseph S. [2 ]
Wang, Xing Li [1 ]
Tang, Dongqi [1 ,2 ]
Cui, Taixing [1 ,2 ]
机构
[1] Shandong Univ, Qilu Hosp, Res Ctr Cell Therapy, Key Lab Cardiovasc Remodeling & Funct Res, Jinan 250012, Peoples R China
[2] Univ S Carolina, Sch Med, Dept Cell Biol & Anat, Columbia, SC 29208 USA
基金
中国国家自然科学基金;
关键词
PROTEIN-DEGRADATION; OXIDATIVE STRESS; AUTOPHAGY; 3-METHYLADENINE; CARDIOMYOCYTES; INHIBITION; INDUCTION; PATHWAYS; DEATH;
D O I
10.1155/2014/748524
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
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页数:15
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