Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway

被引:84
作者
Kim, Kyoung-Han
Oudit, Gavin Y.
Backx, Peter H.
机构
[1] Univ Toronto, Univ Hlth Network, Heart Stroke Richard Lewar Ctr Excellence, Dept Physiol,Div Cardiol, Toronto, ON, Canada
[2] Univ Toronto, Univ Hlth Network, Heart & Stroke Richard Lewar Ctr Excellence, Dept Med,Div Cardiol, Toronto, ON, Canada
关键词
D O I
10.1124/jpet.107.125773
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 mu M). EPO protected against DOX-induced cardiomyocyte death (by similar to 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 (similar to 2-fold) and glycogen synthase kinase 3 (GSK-3; similar to 1.3-fold) phosphorylations, suggesting protection by EPO was mediated by phosphatidylinositol 3-kinase activation. Indeed, preventing Akt and GSK-3 beta 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.
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收藏
页码:160 / 169
页数:10
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