Abstract 3780: Erythropoietin Prevents Cardiac Remodeling after Myocardial Infarction through Erythropoietin Receptor-Induced Signaling Pathways in Cardiomyocytes
Background: Erythropoietin (EPO) has been reported to exert beneficial effects in the treatment of myocardial infarction (MI) through mobilizing bone marrow (BM)-derived cells and promoting vascularization, but the precise mechanisms underlying the protective effects are unknown.
Methods and Results: MI was produced in wild type mice and subcutaneous injection of EPO was started immediately after MI and continued daily for 5 days. EPO inhibited left ventricular dysfunction and reduced infarct size at 2 weeks after MI (p<0.01, n=10). In border area of infarcted hearts, EPO markedly decreased the number of TUNEL-positive apoptotic cells and increased the number of CD31-positive microvessels (p<0.01, n=10). In cultured cardiomyocytes, EPO activated Akt and ERK signaling pathways leading to the attenuation of oxidative stress-induced apoptosis by regulating apoptosis-related proteins such as Bcl-2 family and caspase3, and the antiapoptotic effect was blocked by PI3K and MEK inhibitors or transduction of the dominant negative (dn)-EPO receptor. EPO also increased expression level of VEGF in cardiomyocytes, and conditioned medium of EPO-treated cardiomyocytes enhanced BrdU incorporation in HUVECs (~1.6 folds vs control group), but this endothelial proliferative effect was repressed by VEGF inhibitor or transduction of the dn-Akt and dn-EPO receptor. The introduction of a soluble form of Flt-1, an inhibitor of VEGF in vivo, consistently reduced EPO-induced cardioprotective and angiogenetic effects after MI. While the beneficial effects of EPO were abolished in transgene-rescued EPO receptor null mutant (RES) mice, which lack EPO receptor in nonhematopoietic tissues, and even in RES mice whose BM cells were replaced by them of wild type mice. Moreover, in wild type mice transplanted GFP-expressing BM cells, EPO did not increase the number of GFP positive cells in the infarcted hearts.
Conclusions: These results suggest that EPO prevents left ventricular remodeling after MI by acting on the cardiomyocytes through the EPO-EPO receptor system rather than recruiting BM cells. EPO-induced expression of VEGF in the cardiomyocytes plays a critical role in the vascularization, leading to the protective network between the cardiomyocytes and vessels.