RT Journal Article
SR Electronic
T1 Erythropoietin Protects against Doxorubicin-Induced Cardiomyopathy via a Phosphatidylinositol 3-Kinase-Dependent Pathway
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 160
OP 169
DO 10.1124/jpet.107.125773
VO 324
IS 1
A1 Kyoung-Han Kim
A1 Gavin Y. Oudit
A1 Peter H. Backx
YR 2008
UL http://jpet.aspetjournals.org/content/324/1/160.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics