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Doxorubicin-induced nitrosative stress is mitigated by vitamin C via the modulation of nitric oxide synthases.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2017 Apr 01; Vol. 312 (4), pp. C418-C427. Date of Electronic Publication: 2017 Jan 18. - Publication Year :
- 2017
-
Abstract
- 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-α and IL-10 in isolated cardiomyocytes. Cardiomyocytes isolated from adult Sprague-Dawley rats were segregated into four groups: 1 ) control, 2 ) Vit C (25 µM), 3 ) Dox (10 µM), and 4 ) Vit C + Dox. Dox caused a significant increase in the generation of superoxide radical (O <subscript>2</subscript> <superscript>·-</superscript> ), 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 <subscript>2</subscript> <superscript>·-</superscript> , 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 TNFα 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.<br /> (Copyright © 2017 the American Physiological Society.)
- Subjects :
- Animals
Antibiotics, Antineoplastic administration & dosage
Cells, Cultured
Dose-Response Relationship, Drug
Gene Expression Regulation, Enzymologic drug effects
Gene Expression Regulation, Enzymologic physiology
Male
Myocytes, Cardiac drug effects
Oxidative Stress drug effects
Rats
Rats, Sprague-Dawley
Reactive Nitrogen Species metabolism
Reactive Oxygen Species metabolism
Ascorbic Acid metabolism
Doxorubicin administration & dosage
Myocytes, Cardiac metabolism
Nitric Oxide metabolism
Nitric Oxide Synthase metabolism
Oxidative Stress physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1563
- Volume :
- 312
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 28100487
- Full Text :
- https://doi.org/10.1152/ajpcell.00356.2016