Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy.
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.


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-alpha or transforming growth factor-beta1. 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.
Li
Longhu
L
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu 501-1194, Japan.
Takemura
Genzou
G
Li
Yiwen
Y
Miyata
Shusaku
S
Esaki
Masayasu
M
Okada
Hideshi
H
Kanamori
Hiromitsu
H
Khai
Ngin Cin
NC
Maruyama
Rumi
R
Ogino
Atsushi
A
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D000903:Antibiotics, Antineoplastic; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004317:Doxorubicin; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000097:blood / Q000494:pharmacology*; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control
D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D050991:GATA4 Transcription Factor; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D004317:Doxorubicin; D051546:Cyclooxygenase 2; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases