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Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway.
J Pharmacol Exp Ther. 2008 Jan; 324(1):160-9.JP

Abstract

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 microM). EPO protected against DOX-induced cardiomyocyte death (by approximately 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 (approximately 2-fold) and glycogen synthase kinase 3 (GSK-3; approximately 1.3-fold) phosphorylations, suggesting protection by EPO was mediated by phosphatidylinositol 3-kinase activation. Indeed, preventing Akt and GSK-3beta 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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17928571

Citation

Kim, Kyoung-Han, et al. "Erythropoietin Protects Against Doxorubicin-induced Cardiomyopathy Via a Phosphatidylinositol 3-kinase-dependent Pathway." The Journal of Pharmacology and Experimental Therapeutics, vol. 324, no. 1, 2008, pp. 160-9.
Kim KH, Oudit GY, Backx PH. Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. J Pharmacol Exp Ther. 2008;324(1):160-9.
Kim, K. H., Oudit, G. Y., & Backx, P. H. (2008). Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. The Journal of Pharmacology and Experimental Therapeutics, 324(1), 160-9.
Kim KH, Oudit GY, Backx PH. Erythropoietin Protects Against Doxorubicin-induced Cardiomyopathy Via a Phosphatidylinositol 3-kinase-dependent Pathway. J Pharmacol Exp Ther. 2008;324(1):160-9. PubMed PMID: 17928571.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. AU - Kim,Kyoung-Han, AU - Oudit,Gavin Y, AU - Backx,Peter H, Y1 - 2007/10/10/ PY - 2007/10/12/pubmed PY - 2008/1/19/medline PY - 2007/10/12/entrez SP - 160 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 324 IS - 1 N2 - 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 microM). EPO protected against DOX-induced cardiomyocyte death (by approximately 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 (approximately 2-fold) and glycogen synthase kinase 3 (GSK-3; approximately 1.3-fold) phosphorylations, suggesting protection by EPO was mediated by phosphatidylinositol 3-kinase activation. Indeed, preventing Akt and GSK-3beta 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/17928571/Erythropoietin_protects_against_doxorubicin_induced_cardiomyopathy_via_a_phosphatidylinositol_3_kinase_dependent_pathway_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17928571 DB - PRIME DP - Unbound Medicine ER -