Abstract: OBJECTIVE To investigate the effect of sphingosine 1-phosphate (S1P) on cell apoptosis induced by myocardial ischemia/reperfusion injury(MIRI), and its correlation with PI3K/Akt/GSK3β pathway.METHODS Rats were subjected to MIRI, consisting of 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size and apoptotic index were measured by triphenyltetrazolium (TTC) and terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL) assays, respectively. Plasma CK-MB activity was measured by enzyme linked immunosorbent assay. Akt and GSK3β phosphorylation, caspase-3 cleavage, and cytochrome C translocation were assessed by western blot.RESULTS S1P significantly decreased myocardial infarct size and apoptosis, as well as enhanced Akt and GSK3β phosphorylation, attenuated caspase-3 cleavage and cytosolic cytochrome C translocation. Moreover, the protective effects of S1P treatment were blocked by cotreatment with a PI3K inhibitor, LY294002.CONCLUSION S1P can inhibit the release of mitochondrial cytochrome C, block activation of caspase-3, relieve cellular apoptosis and myocardial infarction. And these effects are mediated by activation of PI3K/Akt/GSK3β pathway.