title: Subcellular basis of vitamin C protection against doxorubicin-induced changes in rat cardiomyocytes.
abstract: Understanding the molecular basis of doxorubicin (Dox)-induced cardiomyopathy is crucial to finding cardioprotective strategies. Oxidative stress-mediated pathways are known to contribute to cardiomyocyte apoptosis due to Dox. Improving the antioxidant defenses of cardiomyocytes could be one strategy for cardiac protection. We tested the effects of vitamin C (Vit C), a potent antioxidant, on Dox-induced cardiomyocyte apoptosis. Adult rat cardiomyocytes were incubated for 24 h with Dox (0.01-10 μM), with and without different concentrations of Vit C (5-100 μM). Exposure to Dox (10 μM) resulted in a 98% increase in the production of reactive oxygen species (ROS) and creatine kinase (CK) release, 70% increase in p53 as well as ASK-1 activation, 40% increase in p38 activation, 30% increase in pro-apoptotic Bax over anti-apoptotic Bcl-xl ratio and caspase activation, and about 20% reduction in cell viability. Vit C (25 μM) was able to mitigate Dox-induced changes by decreasing ROS and CK release by 50%, reducing p53 activation by 40%. The increase in ASK-1 and p38 was also significantly mitigated, and apoptosis was reduced while cardiomyocytes viability was improved. This study shows that Dox-induced cardiomyocyte death is mediated by a direct membrane effect as well as intracytoplasmic changes promoting the cardiomyocyte apoptosis. These findings suggest a nutritional approach of using Vit C for preventing Dox-induced cardiotoxicity and better management of cancer patients.
authors.affiliation: Department of Physiology, Faculty of Medicine, St Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Ludke
authors.forename: Anita K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Bagchi
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004789:Enzyme Activation; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D003402:Creatine Kinase; D001205:Ascorbic Acid