Molecular and Cellular Biochemistry

, Volume 360, Issue 1–2, pp 215–224 | Cite as

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

  • Ana Ludke
  • Anita K. Sharma
  • Ashim K. Bagchi
  • Pawan K. Singal
Article
First Online:
Received:
Accepted:

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.

Keywords

Oxidative stress Cardiomyocyte apoptosis Mitogen-activated protein kinase Cell viability 
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Notes

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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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Ana Ludke
    • 1
  • Anita K. Sharma
    • 1
  • Ashim K. Bagchi
    • 1
  • Pawan K. Singal
    • 1
  1. 1.Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St Boniface Hospital Research CentreUniversity of ManitobaManitobaCanada

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