Aims: Doxorubicin (Dox) is a potent chemotherapeutic agent associated with severe cardiotoxicity. Erythropoietin (Epo) has recently been shown to exhibit proangiogenic properties related to endothelial progenitor cell (EPC) mobilization. We tested the hypothesis that EPC are compromised in rats with Dox-induced cardiotoxicity and correction of this functional impairment by treatment with Epo could result in attenuation of myocardial dysfunction.
Methods and results: Wistar rats were either treated with two different doses of Epo (20U or 200U) or PBS (n = 40 in each group) for four consecutive weeks, followed by Dox administration. In a second study, EPC obtained from healthy rats were transfused intravenously (n = 20/group) prior to induction of Dox cardiomyopathy. EPC from healthy subjects were evaluated for their proliferative and migratory properties in the presence or absence of Dox and Epo pre-treatment. Echocardiography demonstrated an improvement in fractional shortening (FS) in Epo-treated rats. Epo treatment was associated with a reduced mortality in both Epo-treated groups. Circulating EPC numbers were three times higher in Epo-treated compared with non-treated animals. Adhesive properties, migration, and tube formation capacity in matrigel of EPCs from both Epo-treated groups as compared with controls were significantly enhanced. EPC transfer to Dox-treated rats led to functional myocardial improvement equivalent to the protection afforded by treatment with Epo. In EPC obtained from humans, pre-incubation with Epo significantly attenuated the anti-proliferative and anti-migratory effects of treatment with Dox.
Conclusion: Epo treatment is potentially protective against myocardial dysfunction induced by Dox. These effects are partially mediated by enhancement in the number of EPC and their functional properties.