Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism

Background. Erythropoietin (EPO) and carbamylated erythropoietin (CEPO) can Protect tissue from injury; however, CEPO has its protective effect in the absence of erythropoietic stimulation. The mechanism whereby CEPO protects heart from acute ischemia/reperfusion (I/R) injury remains unknown. Methods. BALB/c mice were subjected to myocardial ischemia for 45 min followed by reperfusion for 4 h, and they received a single dose of CEPO intraperitoneal at the onset of reperfusion. Myocardial infarct size and cardiac function were assessed. The association of erythropoietin receptor with g common receptor (beta cR) was examined. The level of Akt phosphorylation in the myocardium was assayed as well as a series of downstream target genes of PI3K/Akt, including p-GATA-4, GATA-4, MHC, and troponin I. Results. CEPO administration immediately before reperfusion decreased infarction by 40% and increased ejection fraction (27%) and fractional shortening (22%), compared with untreated ischemic hearts (P < .05 each). CEPO promoted association of the EPO receptor and beta cR. Furthermore, CEPO administration increased the levels of phospho-Akt in the myocardium by 59% (P < .05). A PI3K inhibitor, wortmannin, blocked the beneficial effect of CEPO on infarct size and cardiac function and attenuated the CEPO-induced Akt phosphorylation. CEPO also increased the expression of p-GATA-4, GATA-4, myosin heavy chain, and troponin I. Conclusion. A single dose of CEPO at the onset of reperfusion attenuated acute myocardial I/R injury in the mouse. CEPO-induced cardioprotection appears to be mediated through a PI3K/Akt-dependent mechanism. (Surgery 2009;146.-506-14.)