Abstract 1433: Erythropoietin (Epo) Has Direct Cardioprotective Effects on Post-MI Hearts through Epo-Epo Receptor System in Cardiomyocytes
Background-Erythropoietin (Epo) has been reported to reduce infarct size and prevent remodeling after acute myocardial infarction (MI), but the exact mechanism is unknown.
Methods-Wild-type (WT) mice and transgenic-rescued Epo receptor null mutant (KO) mice, which lack Epo receptor in nonhematopoietic tissues, were induced MI by ligation of left coronary artery and randomized into 4 groups; WT-Epo-treated (WT-E) group (n=13), WT-saline-treated (WT-C) group (n=15), KO-Epo-treated (KO-E) group (n=20), KO-saline-treated (KO-C) group (n=20). In Epo-treated groups, subcutaneous injection of Epo was started immediately after MI and continued daily for 5 days. At 2 weeks after MI, we evaluated cardiac function using echocardiography and assessed the morphology by histological analysis. We performed TUNEL staining and western blotting using the post-MI hearts. Furthermore, we transplanted bone marrow cells of GFP transgenic mice into WT mice and produced MI to examine the contribution of bone marrow cells mobilized by Epo.
Results-Epo significantly inhibited left ventricular (LV) remodeling and LV dysfunction after MI in WT mice (LV end-systolic diameter, WT-E group: 5.1±0.12 mm, WT-C group: 5.8±0.19 mm, p<0.01; fractional shortening, WT-E group: 39.2±9.3%, WT-C group: 65.7±12.2%, p<0.01). And Epo significantly reduced the percentage of infarct area to LV free wall area in WT mice (WT-E group: 39.2±9.3%, WT-C group: 65.7±12.2%, p<0.01). These effects by Epo were not recognized in KO mice. The number of TUNEL-positive cells was more decreased and the number of capillary vessels was more increased in WT-E group than WT-C group. These effects by Epo were not observed in KO mice. Epo markedly increased the activity of Akt and the expression level of VEGF in the hearts of WT-E group, but not in the hearts of other groups. The number of GFP-positive cells in the post-MI hearts was not different between WT-C group and WT-E group.
Conclusions-These results suggest that Epo directly acts on post-MI hearts through Epo-Epo receptor system and activates intracellular signal pathways. Epo decreases apoptotic cell death and increases capillary vessels, resulting in the prevention of LV remodeling and LV dysfunction.