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dc.contributor.supervisorSingal, Pawan (Physiology and Pathophysiology) Jassal, Davinder (Physiology and Pathophysiology)en_US
dc.contributor.authorAkolkar, Gauri
dc.date.accessioned2017-08-23T16:41:39Z
dc.date.available2017-08-23T16:41:39Z
dc.date.issued2017en_US
dc.date.issued2017en_US
dc.identifier.citationG Akolkar, A.K Bagchi, P Ayyappan, D. S. Jassal, and P. K. Singal. Doxorubicin induced nitrosative stress is mitigated by vitamin C via the modulation of nitric oxide synthases. American Journal of Physiology.Cell Physiology 312: 418-427, 2017.en_US
dc.identifier.citationG Akolkar, D Dias, P Ayyappan, A. K Bagchi, D. S Jassal, V M Salemi, M C Irigoyen, K DeAngelis, P K. Singal. Attenuation of oxidative/nitrosative stress and inflammation by Vitamin C in Doxorubicin-induced cardiomyopathy; American Journal of physiology – heart and circulatory physiology (In press) 2017.en_US
dc.identifier.urihttp://hdl.handle.net/1993/32366
dc.description.abstractDoxorubicin (Dox) cardiotoxicity is a serious concern in its use for the treatment of cancers. Oxidative stress (OS) and nitrosative stress (NS) are suggested to be the main causes of this cardiotoxicity. We used rat cardiomyocytes as well as whole animals to characterize changes in Dox-induced apoptosis, inflammation, OS/NS, cardiac structure/function and Vitamin C (Vit C) transporter proteins and the mitigation of these effects by Vit C. In cardiomyocytes, Dox (10 µM) caused an increase in both superoxide radical and Nitric oxide (NO), resulting in the generation of peroxynitrite, protein nitration and nitrosylation. Dox increased Nitric oxide synthase (NOS) activity via the upregulated protein expression of inducible NOS (iNOS) and the altered protein expression as well as activation of endothelial NOS (eNOS). Dox also reduced the stability of dimeric eNOS and increased ratio of monomeric/dimeric eNOS. Dox-induced increase in TNF-α and a reduction in IL-10 was also noted. These Dox-mediated alterations in cardiomyocytes were attenuated by Vit C (25 µM) pretreatment. In the rat model of Dox-induced cardiotoxicity (cumulative dose, 15mg/kg), both systolic and diastolic functions were decreased and there was structural damage in hearts. These changes were associated with increased levels of myocardial reactive oxygen species; reduction in anti-oxidant enzyme activities (SOD, GPx and catalase); increased expression of apoptotic proteins (Bax, Bnip-3, Bak and Caspase-3) and inflammation. An increase in OS/NS was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, NO, NOS activity, protein nitrosylation and iNOS expression. Dox increased the levels of cardiac TNF-α, IL-1β and IL-6 while the expression of Vit C transporter proteins (SVCT-2 and Glut-4) was reduced. Vit C (50 mg/kg) prevented all these changes, improved Dox-mediated systolic and diastolic dysfunctions, prevented structural damage and improved animal survival. These results suggest that Vit C provides cardioprotection by reducing OS/NS as well as inflammation via modulation of Dox-induced increase in the NO levels and NOS activity. The molecular details in this study provide a rationale for a prophylactic use of Vit C to reduce chemotherapy induced cardiotoxicity.en_US
dc.language.isoengen_US
dc.publisherAmerican Physiological Societyen_US
dc.publisherAmerican Physiological Societyen_US
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectoxidative stressen_US
dc.subjectdoxorubicinen_US
dc.subjectantioxidanten_US
dc.subjectcardiotoxicityen_US
dc.subjectVitamin Cen_US
dc.titleCardioprotective role of vitamin C in the mitigation of oxidative/nitrosative stress in doxorubicin-induced cardiotoxicityen_US
dc.typeinfo:eu-repo/semantics/doctoralThesis
dc.typedoctoral thesisen_US
dc.degree.disciplinePhysiology and Pathophysiologyen_US
dc.contributor.examiningcommitteeKirshenbaum, Lorrie (Physiology and Pathophysiology) Dhalla, Naranjan (Physiology and Pathophysiology) Wigle, Jeffery (Biochemistry and Medical genetics) Bkaily, Ghassan (Université de Sherbrooke)en_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.noteOctober 2017en_US


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