involvement of the foxo3a pathway in the ischemiareperfusion injury of cardiac microvascular endothelial cells foxo3a a member of the forkhead transcription factors has been demonstrated to be involved in myocardial ischemiareperfusion ir injury cardiac microvascular endothelial cells cmecs are some of the predominant cells damaged immediately after myocardial ir injury despite the importance of injured cmecs in an ischemic heart little is known about the involvement of foxo3a in regulating cmecs injury thus we used rat cmecs following simulated ir to examine foxo3a activation and signaling in relation to survival the cell cycle and apoptosis in cmecs we found that akt negatively regulates activation of the foxo3a pathway by phosphorylating foxo3a in cmecs as demonstrated with an akt inhibitor and activator upon ir injury the foxo3a pathway was significantly activated in cmecs which was accompanied by akt deactivation in parallel the ir of cmecs induced g1phase arrest through p27kip1 upregulation and significant activation of caspase3 accordingly inhibition of the foxo3a pathway by igf1 an akt activator could significantly block the irenhanced activation of p27kip1 and caspase3 in cmecs collectively our results indicate that the foxo3a pathway is involved in the ir injury of cmecs at least in part through the regulation of cell cycle arrest and apoptosis suggesting that the foxo3a pathway may be a novel therapeutic target that protects against microvascular endothelial damage in ischemic hearts