Effects of Combination of Proliferative Agents and Erythropoietin on Left Ventricular Remodeling Post-Myocardial Infarction

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post-myocardial infarction (MI) effects synergistically. Methods: After MI, five to seven animals were randomly assigned to each of the following treatments: control; hCG; EPO; hCG + EPO, and prolactin (PRL) + EPO. Follow-up echocardiograms were performed to assess cardiac structure and function. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and western blot analysis for apoptosis-related proteins, and cell proliferation by immunostaining for Ki67 and c-kit cells. Results: The MI-mediated increased chamber systolic dimension (p < 0.05 in controls) was attenuated by hCG, EPO, and hCG + EPO (p < 0.05 vs. control) but not PRL + EPO. Similarly all treatment groups, except PRL + EPO, reduced MI-induced increases (p < 0.05 vs. control) in ejection fraction (EF). The functional improvement in the EPO-treated groups was accompanied by increased capillary density. Apoptosis was markedly reduced in all treated groups. Significantly more cardiac c-kit⁺ cells were found in the hCG + EPO group. Conclusion: Our findings revealed that EPO, hCG, or their combination ameliorate cardiac remodeling post-MI. Whereas EPO stimulates neovascularization only and hCG + EPO stimulates c-kit+ cell proliferation. These data suggest that combining mobilizing and proliferative agents adds to the durability and sustainability of cytokine-based therapies for remodeling post-MI.