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Subcellular basis of vitamin C protection against doxorubicin-induced changes in rat cardiomyocytes

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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.

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Acknowledgment

The support from the Canadian Circulatory and Respiratory Institute (Dr. Singal) is greatly acknowledged. Mrs. Ana Ludke is supported by a studentship from Manitoba Health Research Council. Dr. Pawan Singal is holder of the Naranjan Dhalla Chair in Cardiovascular Research supported by the St. Boniface Hospital and Research Foundation.

Conflict of Interest

The authors have declared no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St Boniface Hospital Research Centre, University of Manitoba, 351 Tache Ave, Room R3021 Winnipeg, Manitoba, R2H 2A6, Canada

    Ana Ludke, Anita K. Sharma, Ashim K. Bagchi & Pawan K. Singal

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  1. Ana Ludke
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  2. Anita K. Sharma
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  3. Ashim K. Bagchi
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  4. Pawan K. Singal
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Correspondence to Pawan K. Singal.

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Ludke, A., Sharma, A.K., Bagchi, A.K. et al. Subcellular basis of vitamin C protection against doxorubicin-induced changes in rat cardiomyocytes. Mol Cell Biochem 360, 215–224 (2012). https://doi.org/10.1007/s11010-011-1059-z

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  • DOI: https://doi.org/10.1007/s11010-011-1059-z

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