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(Circulation. 2006;113:535-543.)
© 2006 American Heart Association, Inc.

Heart Failure

Preventive Effect of Erythropoietin on Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy

Longhu Li, MD; Genzou Takemura, MD; Yiwen Li, MD; Shusaku Miyata, MD; Masayasu Esaki, MD; Hideshi Okada, MD; Hiromitsu Kanamori, MD; Ngin Cin Khai, MD; Rumi Maruyama, BS; Atsushi Ogino, MD; Shinya Minatoguchi, MD; Takako Fujiwara, MD; Hisayoshi Fujiwara, MD

From the Second Department of Internal Medicine (L.L., G.T., Y.L., S.M., M.E., H.O., H.K., N.C.K., R.M., A.O., S.M., H.F.), Gifu University School of Medicine, Gifu, Japan, and the Department of Food Science (T.F.), Kyoto Women’s University, Kyoto, Japan.

Correspondence to Hisayoshi Fujiwara, MD, PhD, Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. E-mail gifuim-gif{at}umin.ac.jp

Received June 12, 2005; revision received October 30, 2005; accepted November 14, 2005.

Background— Doxorubicin is a highly effective antineoplastic drug, but its clinical use is limited by its adverse side effects on the heart. We investigated possible protective effects of erythropoietin against doxorubicin-induced cardiomyopathy.

Methods and Results— Cardiomyopathy was induced in mice by a single intraperitoneal injection of doxorubicin (15 mg/kg). In some cases, human recombinant erythropoietin (5000 U/kg) was started simultaneously. Two weeks later, left ventricular dilatation and dysfunction were apparent in mice given doxorubicin but were significantly attenuated by erythropoietin treatment. Erythropoietin also protected hearts against doxorubicin-induced cardiomyocyte atrophy and degeneration, myocardial fibrosis, inflammatory cell infiltration, and downregulation of expression of GATA-4 and 3 sarcomeric proteins, myosin heavy chain, troponin I, and desmin. Cyclooxygenase-2 expression was upregulated in doxorubicin-treated hearts, and that, too, was attenuated by erythropoietin. No doxorubicin-induced apoptotic effects were seen, nor were any changes seen in the expression of tumor necrosis factor- or transforming growth factor-ß1. Antiatrophic and GATA-4 restoring effects of erythropoietin were demonstrated in the in vitro experiments with cultured cardiomyocytes exposed to doxorubicin, which indicated the direct cardioprotective effects of erythropoietin beyond erythropoiesis. Cardiac erythropoietin receptor expression was downregulated in doxorubicin-induced cardiomyopathy but was restored by erythropoietin. Among the downstream mediators of erythropoietin receptor signaling, activation of extracellular signal-regulated kinase was reduced by doxorubicin but restored by erythropoietin. By contrast, erythropoietin was ineffective when administered after cardiac dysfunction was established in the chronic stage.

Conclusions— The present study indicates a protective effect of erythropoietin against doxorubicin-induced cardiomyopathy.

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