Doxorubicin-induced nitrosative stress is mitigated by vitamin C via the modulation of nitric oxide synthases

被引:44
作者
Akolkar, Gauri [1 ]
Bagchi, Ashim K. [1 ]
Ayyappan, Prathapan [1 ]
Jassal, Davinder S. [1 ]
Singal, Pawan K. [1 ]
机构
[1] Univ Manitoba, St Boniface Hosp Albrechtsen, Dept Physiol & Pathophysiol,Res Ctr, Max Rady Coll Med,Rady Fac Hlth Sci,Inst Cardiova, Winnipeg, MB, Canada
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2017年 / 312卷 / 04期
基金
加拿大健康研究院;
关键词
oxidative stress; nitrosative stress; nitric oxide synthase; doxorubicin; vitamin C; ascorbic acid; INDUCED CARDIOTOXICITY; INDUCED CARDIOMYOPATHY; S-NITROSYLATION; MOLECULAR-MECHANISMS; CANCER-PATIENTS; THERAPEUTIC STRATEGIES; ANTIOXIDANT ENZYMES; OXIDATIVE STRESS; HEART-FAILURE; IN-VITRO;
D O I
10.1152/ajpcell.00356.2016
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
An increase in oxidative stress is suggested to be the main cause in Doxorubicin (Dox)-induced cardiotoxicity. However, there is now evidence that activation of inducible nitric oxide synthase (iNOS) and nitrosative stress are also involved. The role of vitamin C (Vit C) in the regulation of nitric oxide synthase (NOS) and reduction of nitrosative stress in Dox-induced cardiotoxicity is unknown. The present study investigated the effects of Vit C in the mitigation of Dox-induced changes in the levels of nitric oxide (NO), NOS activity, protein expression of NOS isoforms, and nitrosative stress as well as cytokines TNF-alpha and IL-10 in isolated cardiomyocytes. Cardiomyocytes isolated from adult Sprague-Dawley rats were segregated into four groups: 1) control, 2) Vit C (25 mu M), 3) Dox (10 mu M), and 4) Vit C + Dox. Dox caused a significant increase in the generation of superoxide radical (O-2(.-)), peroxynitrite, and NO, and these effects of Dox were blunted by Vit C. Dox increased the expression of iNOS and altered protein expression as well as activation of endothelial NOS (eNOS). These changes were prevented by Vit C. Dox induced an increase in the ratio of monomeric/ dimeric eNOS, promoting the production of O-2(.-), which was prevented by Vit C by increasing the stability of the dimeric form of eNOS. Vit C protected against the Dox-induced increase in TNF alpha as well as a reduction in IL-10. These results suggest that Vit C provides cardioprotection by reducing oxidative/nitrosative stress and inflammation via a modulation of Dox-induced increase in the NO levels and NOS activity.
引用
收藏
页码:C418 / C427
页数:10
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