Abstract 609: Erythropoietin-Mediated Protection Against Hypoxia/Reoxygenation Injury in Human Muscle is via Phosphatidylinositol-3-Kinase and P42/44 Kinase Activation
The renal cytokine Erythropoietin (EPO) has in animal studies demonstrated myocardial protection, this being linked to the activation of pro-survival signalling cascades, phosphatidylinositol-3-kinase (PI3K) and p42/44 extra-cellular signal-regulated kinases. This protection and the mechanisms associated with it have to date not been observed in human myocardium. We investigated the ability of EPO to protect human atrial trabeculae obtained from patients undergoing coronary artery bypass surgery. Since PI3K has been shown to be down regulated in diabetic animal studies we also examined the ability of EPO to protect human muscle from type 2 diabetic patients. Isolated human atrial trabeculae were suspended in an organ bath and exposed to 90 minutes of hypoxia followed by 120 minutes of reoxygenation. EPO (50ng/ml) was administered throughout reoxygenation following simulated ischemia. Cardiac function was assessed by measuring the developed force of contraction which was calculated as a percentage of baseline force of contraction. EPO improved force of contraction when administered at reoxygenation (46.7% +/− 1.7 vs. 30.2% +/− 2.2 for control, p< 0.001). These effects were abrogated by the PI3K inhibitor, LY294002 (29.4% +/− 2.5 vs. 30.2% +/−2.2 for control) and P42/44 inhibitor, UO126 (31.5% +/− 2.5 vs. 30.2% +/− 2.2 for control). EPO and preconditioning (as a positive control) offered similar degrees of protection (46.7% +/− 1.8 vs. 51.2% +/− 1.4 for preconditioning). In the diabetic group, EPO improved force of contraction (38.3% +/− 1.4 vs. 30.2% +/− 2.2 for control, p<0.05). However, the degree of cardioprotection was less than that observed in the non diabetic group (38.3% +/− 1.4 vs. 46.7% +/− 1.7 for non diabetic EPO group, p<0.005). EPO administered at reoxygenation protects the human muscle via the PI3K and P42/44 dependent pathways. Inhibiton of either pro-survival kinase results in loss of cardiac protection. EPO cardioprotection was also observed in the diabetic group, although still significant, was not of the same magnitude as observed in the non diabetic group. This data supports the potential use of EPO as a novel cardioprotective strategy when used alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.