Abstract 1387: Post-Infarct Treatment with an Erythropoietin-Gelatin Hydrogel Drug Delivery System Promotes Cardiac Repair by Activating Prosurvival Signaling and Exerting Antifibrotic and Angiogenic Effects
Erythropoietin (EPO) has been reported to protect ischemic myocardium. However, the effective dose of EPO is too high to administer clinically. We hypothesized that an EPO-gelatin hydrogel patch applied to the heart would be beneficial for myocardial infarction without causing any side effects. Rabbits underwent 30min of coronary occlusion followed by 14 days and 2 months of reperfusion. In the Saline and Systemic groups, saline or 1500IU/kg of EPO (Systemic group) was subcutaneously injected after reperfusion once/day for 5 days (Totally 7500 IU/kg of EPO), respectively. In the EPO-DDS group, a EPO-containing (1500 IU/kg) gelatin hydrogel sheet, which releases EPO continuously over 14 days was applied to the myocardial surface of the risk area. Left ventricular (LV) function, ±dp/dt, fibrotic areas and the infarct size were determined. The number of CD31-positive microvessels and Erythropoietin-receptor (EPOR), Akt, Glycogen Synthase kinase-3β (GSK-3β), Stat3, ERK, Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinase-1 (MMP-1) were analysed. Ejection fraction, fractional shortening and LV dimension in the EPO-DDS group were significantly improved compared to those in the other groups 14 days and 2 month post-MI. On day 14, the infarct size and fibrotic areas were significantly reduced in the EPO-DDS group but not in the Systemic nor Saline group. Hematocrit was significantly increased in the Systemic group but not in the EPO-DDS group. The number of CD31-positive microvessels was significantly increased in the EPO-DDS group. The expressions of EPOR, Akt, GSK-3β, Stat3, ERK, VEGF and MMP-1 protein were markedly increased in the EPO-DDS group on day 2 post-Myocardial Infarction (MI). Moreover, EPOR, p-Akt, p-ERK and MMP-1 were still significantly increased in the EPO-DDS group on day 14 post-MI. The cardiac EPO-gelatin hydrogel Drug Delivery System, but not systemically administered EPO, reduced MI size and improved LV remodeling and function without adverse side effects (e.g., erythropoiesis) through the activation of prosurvival mediators such as Stat3, Akt, ERK, GSK-3β and Bcl-2, and by exerting antifibrotic and angiogenic effects through the activation MMP-1 and VEGF.