Abstract 1061: Erythropoietin Prevents Cardiac Remodeling After Myocardial Infarction Through Erythropoietin Receptor-induced Signaling Pathways in Cardiomyocytes
Background: Erythropoietin (EPO) has been reported to improve cardiac function after myocardial infarction (MI) through promoting mobilization of endothelial progenitor cells to the injured heart and enhancing neovascularization. However, the precise mechanisms of the beneficial effects of EPO against MI are unknown. In this study, we investigated the molecular mechanisms of how EPO prevents left ventricular (LV) remodeling after MI.
Methods: We produced MI in wild type (WT) mice and transgene-rescued EPO receptor null mutant (RES) mice, which lack EPO receptor in nonhematopoietic tissues. We also produced MI in transgenic mice which express dominant-negative STAT3 in cardiomyocytes (dnSTAT3-tg) and in the mice of which bone marrow (BM) was replaced by BM cells of enhanced green fluorescent protein-expressing mice. We examined anti-apoptotic effects of EPO in cultured neonatal rat cardiomyocytes.
Results: EPO significantly prevented LV dysfunction and reduced infarct size after MI in WT mice but not RES mice (p<0.01, n=10). EPO decreased the number of apoptotic cells and increased the capillary density after MI in WT mice but not RES mice (p<0.01, n=10). EPO activated Akt and ERK and increased VEGF in post-MI hearts. There were no differences in LV function and infarct size after MI between EPO-treated dnSTAT3-tg mice and WT mice. Although the number of circulating CD34+/Flk-1+ cells was increased by EPO after MI in WT mice but not RES mice, EPO did not increase the number of BM-derived cells in the post-MI hearts. EPO was not effective even in RES mice whose BM was replaced by that of WT mice. In cultured cardiomyocytes, EPO activated Akt and ERK signaling and attenuated H2O2-induced apoptosis (~31%, p<0.05, n=8) by regulating apoptosis-related proteins such as Bcl-2 family and caspase3. Furthermore, the cytoprotective effects of EPO were reduced by PI3K and MEK inhibitors or dominant-negative form of EPO receptor, but not by dominant-negative STAT3.
Conclusions: EPO prevents LV remodeling and dysfunction after MI by directly acting on the heart rather than recruiting blood cells. EPO-mediated cardiomyocyte survival may be caused by Akt and ERK activation but not STAT3, which plays a critical role in G-CSF-induced cardioprotection.