Abstract 1063: Intracardiac Injection of Epoetin-α Upregulates Stem Cell Chemoattractant Gene Expression In a Rat Myocardial Infarction Model

Abstract

Emerging evidence suggests that Erythropoietin (EPO) protects the myocardium from ischemic injury and promotes beneficial remodelling. However, the role of EPO and its receptor (EPO-R) in mediating cardiac regeneration remains unclear. We hypothese that stem cell homing and proliferation modulated by EPO could contribute to its cardio-protective effects. Epoetin-α (3000 U/kg) was injected along the infarction border after the induction of a rat myocardial infarction (MI) by permanent ligation of the left descending coronary artery. At six weeks after MI, cardiac function was measured by pressure-volume loops in left and right ventricles. Infarction size, angiogenesis and pathologic effects were evaluated. Gene expressions of EPO-R, SDF-1α, CXCR-4, c-kit, eNOS, TNF-α, IL-8, Integrin-β and CdK4 were analyzed by RT-PCR at different time points of the first week (24h, 48h, 96h and 7 days). We found EPO treatment improved left ventricular function both at baseline levels and under Dobutamine stress (tau, cardiac output, stroke work, ejection fraction, dp/dt maximum and minimum, n=11–14, p<0.05) and decreased right ventricular wall stress (maximum and endsystolic pressure, n=5– 8, p<0.05). Infarction size was reduced from 27.8±3.4% to 20.1±2.8% (n=6 – 8, p<0.01). Capillary density was increased from 257.7±24.5 to 338.5±35.9 (vessels per square mm, n=6 – 8, p<0.05). Mortality was decreased from 29.0% to 22.2% (n=53– 69). EPO-R was down regulated in infarcted, peri-infarcted and non infarcted areas at all time points (n=7, p<0.05). Cardiac SDF-1α, CXCR-4 and eNOS gene expressions were increased at 24 hours. C-kit was up regulated significantly at 48 hours compared to 24 hours in the EPO treated hearts. In untreated hearts, c-kit expression remained constant. Proinflammatory cytokines (TNF-β, IL-8 and Integrin-γ) were down regulated. Cell cycle re-entry marker (CdK4) was increased at 24 hours in non infarcted zones. In conclusion, we demonstrate intramyocardium Epoetin-α injection induces an earlier up regulation of stem cell chemoattractants, reduces inflammation, enhances angiogenesis and restores heart function after MI.