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CARDIOVASCULAR

Erythropoietin Protects against Doxorubicin-Induced Cardiomyopathy via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Departments of Physiology and Medicine, Heart and Stroke/Richard Lewar Centre of Excellence and Division of Cardiology, University Health Network, University of Toronto, Toronto, Ontario, Canada

Doxorubicin (DOX) is an effective antineoplastic agent whose use has been limited by its cardiotoxic side effects. Recent studies have established that erythropoietin (EPO), a cytokine essential for red blood cell production, protects against ischemic injury in the heart and other organs. The purpose of this study was to assess whether EPO protects the heart against cardiotoxicity induced by DOX. We found that DOX-induced apoptosis and impaired heart function in mice were largely prevented by EPO administration. To investigate the mechanism of protection by EPO, cultured neonatal mouse ventricular myocytes were treated with EPO at therapeutic levels (i.e., 1 U/ml), before application of DOX (0.1–1.0 µM). EPO protected against DOX-induced cardiomyocyte death (by 50%) and apoptosis assessed by annexin-V labeling, DNA fragmentation, and caspase-3 activity. DOX-mediated increases in reactive oxygen species, which trigger cardiotoxicity, were also reversed by preconditioning with EPO. These functional effects of EPO correlated with increased Akt/protein kinase B (2-fold) and glycogen synthase kinase 3 (GSK-3; 1.3-fold) phosphorylations, suggesting protection by EPO was mediated by phosphatidylinositol 3-kinase activation. Indeed, preventing Akt and GSK-3β phosphorylations by phosphatidylinositol 3-kinase (PI3K) inhibition abolished protection by EPO against cardiomyocyte loss, apoptosis, and oxidative stress. Thus, pretreatment with therapeutic levels of EPO can protect the myocardium against DOX-induced impaired heart function and cardiomyocyte apoptosis by activating PI3K-Akt cell survival pathways.

Address correspondence to: Dr. Peter H. Backx, Departments of Physiology and Medicine, Heart and Stroke/Richard Lewar Centre of Excellence, Room 71, FitzGerald Bldg. 150 College St., Toronto, ON M5S 3E2, Canada. E-mail: p.backx{at}utoronto.ca