Abstract 844: New Drug Delivery System Using an Erythropoietin Gelatin Hydrogel Sheet Selectively Protects the Heart Against Myocardial Infarction through Activation of Akt and Angiogenesis
Background: Erythropoietin (EPO) has been reported to protect ischemic myocardium. However, the effective dose of EPO is too high to administer clinically. We hypothesized that EPO gelatin hydrogel sheet applied to the heart would be beneficial against myocardial infarction without any side effect.
Methods: Rabbits (male 2kg) underwent 30min of coronary occlusion and 14 days of reperfusion. Saline (control group) or 1500 IU/kg of EPO (EI group) was subcutaneously injected immediately after reperfusion once/day for 5 days (total amount of 7500IU/kg) In the ED group, a patch made from a gelatin hydrogel sheet was applied to myocardial surface of the risk area. The EPO hydrogel sheet contains 1500IU/kg of EPO which is released continuously over 14 days. Left ventricular (LV) function was measured by echocardiography. The infarct size was determined by TTC staining and expressed as a percentage of the risk area. Immunohistochemical analysis was perfomed to examine the number of CD31-positive microvessels. Western blot analysis was performed to examine Akt phosphorylation.
Results: Ejection fraction, fractional shortening and infarcted wall thickness in the ED group were significantly larger than those in the EI and control groups. LV systolic and diastolic dimensions in the ED group were significantly smaller than those in the EI and control groups. The infarct size was significantly reduced in the ED group(13.2±1.9%) but not in the EI group(24.7±1.7%) compared with that in the control group(23.1±2.9%) Hematocrit significantly increased in the EI group but not in the ED group. The number of CD31-positive microvessels was significantly increased in the ED group (319.5±3.2/HPF) compared with those in the EI (260.3±16.1/HPF) and control groups (269.5±11.8/HPF). The expression of P-Akt protein was markedly increased in the ED group as compared with that in the EI group or control group.
Conclusion: EPO gelatin hydrogel sheet but not EPO systemic injection decreases myocardial infarct size and improves LV function and remodeling without any side effect such as erythropoiesis. The mechanism involves activation of Akt and angiogenesis rather than effects on hematopoiesis. These findings provide new insight into therapeutic strategies for ischemic heart disease.