Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol‐3 kinase and ERK1/2 activation

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BACKGROUND AND PURPOSES: Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol-3 kinase (PI3K)/Akt and ERK1/2. However these pro-survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non-diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia-reoxygenation injury. EXPERIMENTAL APPROACH: Human atrial trabeculae were exposed to 90min hypoxia and 120min reoxygenation. EPO was administered throughout reoxygenation. The developed force of contraction, calculated as a percentage of baseline force of contraction, was continuously monitored. The involvement of PI3K and ERK1/2 and the levels of activated caspase 3(AC3) were assessed. KEY RESULTS: EPO improved the force of contraction in tissue from non-diabetic patients (46.7+/-1.7% vs. 30.2+/-2.2% in control, p<0.001). These beneficial effects were prevented by the PI3K inhibitor, LY294002 and the ERK1/2 inhibitor, U0126. EPO also significantly improved the force of contraction in the diabetic tissue, although to a lesser degree. The levels of activated caspase 3 were significantly reduced in EPO treated trabeculae from both non-diabetic and diabetic patients, relative to their respective untreated controls. CONCLUSIONS AND IMPLICATIONS: EPO administered at reoxygenation protected human myocardial muscle by activating PI3K and ERK1/2 and reducing the level of activated caspase 3. This cardioprotection was also observed in the diabetic group. This data supports the potential of EPO being used as a novel cardioprotective strategy either alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.

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