Subcellular basis of vitamin C protection against doxorubicin-induced changes in cardiomyocytes and Sca-1 positive cells

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dc.contributor.supervisor Singal, Pawan (Physiology) en_US
dc.contributor.author Ludke, Ana
dc.date.accessioned 2012-10-25T18:52:25Z
dc.date.available 2012-10-25T18:52:25Z
dc.date.issued 2012 en_US
dc.date.issued 2012 en_US
dc.identifier.citation Ludke A, Sharma AK, Bagchi AK, Singal PK.Subcellular basis of vitamin C protection against doxorubicin-induced changes in rat cardiomyocytes. Mol Cell Biochem. 2012 Jan;360(1-2):215-24. en_US
dc.identifier.citation Ludke AR, Sharma AK, Akolkar G, Bajpai G, Singal PK.Downregulation of vitamin C transporter SVCT-2 in doxorubicin-induced cardiomyocyte injury. Am J Physiol Cell Physiol. 2012 Sep;303(6):C645-53. en_US
dc.identifier.uri http://hdl.handle.net/1993/9677
dc.description.abstract Understanding the molecular basis of doxorubicin (Dox)-induced oxidative stress leading to cardiomyopathy is crucial to finding cardioprotective strategies to manage this important clinical problem. Improving the antioxidant defenses of cardiac cells could be one strategy for cardioprotection. The role of oxidative stress in Dox-induced cardiotoxicity as well as testing the efficacy of antioxidant Vitamin C (Vit C) in offering protection to cardiomyocytes was investigated. As stem cells have been suggested to play a role in this cardiotoxicity, Dox-mediated oxidative stress effects, with and without Vit C, on the stem cell antigen-1 (Sca) positive cells from heart as well as bone marrow were also examined. Our time-course studies of the effects of Dox on the isolated cardiomyocytes showed that the phosphorylation of mitogen-activated protein kinases and p53 followed the rise in reactive oxygen species (ROS) production. Dox also downregulated the Sodium-dependent Vit C Transporter-2 (SVCT-2) and this may have enhanced Dox-induced increase in oxidative stress. Pro-apoptotic markers Bax/Bcl-xL ratio and caspase 3 cleavage were higher after the activation of stress-induced pathways and viability of cells was decreased. Dox-induced increase in apoptosis and decrease in cell viability depended in part on the activation of p38/JNK and p53 proteins, but not on the ERK protein. Exposure to Dox, increased membrane leakage, autophagy and lipid peroxidation. On the other hand, Dox decreased overall antioxidant capacity as well as expression of the endogenous antioxidant enzymes glutathione peroxidase, Cu/Zn superoxide dismutase and catalase. Dox affected Sca-1 positive cells in a prominent manner which was marked by a dose-dependent increase in cell loss, cell leakage and ROS levels as well as decrease in cellular ATP levels. Vit C pre-treatment prior to the addition of Dox delayed and reduced Dox-induced injury to cardiomyocytes, preserving viability. Vit C was able to blunt the decrease in SVCT-2 as well as Dox-induced oxidative stress. Vit C also offered protection to Sca-1 positive cells by partially preventing Dox-induced changes to these cells. The data presented in this thesis improves our knowledge of the molecular mechanisms leading to Dox-induced cardiotoxicity as well as suggest cardioprotection by Vit C. en_US
dc.publisher Springer/Kluwer Academic Publishers en_US
dc.publisher American Physiological Society en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject heart failure en_US
dc.subject apoptosis en_US
dc.subject stem cell en_US
dc.subject chemotherapy en_US
dc.subject oxidative stress en_US
dc.title Subcellular basis of vitamin C protection against doxorubicin-induced changes in cardiomyocytes and Sca-1 positive cells en_US
dc.type info:eu-repo/semantics/doctoralThesis
dc.type doctoral thesis en_US
dc.degree.discipline Physiology en_US
dc.contributor.examiningcommittee Dixon, Ian (Physiology) Kirshenbaum, Lorrie (Physiology) Duhamel, Todd (Kinesiology and Recreation Management) Prasad, Kailash (University of Saskatchewan) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note February 2013 en_US

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