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Postconditioning (PostC) has regenerated interest as a mechanical intervention against myocardial ischemia/reperfusion injury, but its molecular mechanisms remain elusive. This study tested the hypothesis that hypoxia inducible factor-1α (HIF-1α) plays a role in PostC-induced cardioprotection. Male Wistar rats were subjected to 30 min ischemia followed by 3 h of reperfusion (Control). PostC with 3 cycles of 10 s reperfusion and 10 s re-occlusion was applied at the onset of reperfusion. Relative to the Sham group, HIF-1α protein level was increased by 2.9-fold in the Control group, but its level was enhanced by 5.8-fold with PostC ( P < 0.01 vs. Control). However, HIF-1α protein level was further augmented by 2.0-fold and 3.3-fold, respectively, when the prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG, 40 mg/kg, i.p.) was given at 24 h before ischemia in both Control and PostC groups. PostC reduced infarct size by 24% compared with the Control (27 ± 4.2% vs. 36 ± 5.2%, P < 0.01), consistent with significant lower levels of plasma creatine kinase activity, index of cardiomyocyte apoptosis and caspase-3 activity. Although pretreatment with DMOG significantly reduced infarct size relative to the Control, the infarct-sparing effect of PostC was remarkably enhanced when DMOG was given before PostC (18 ± 2.0% vs. 27 ± 4.2% in PostC alone, P < 0.05). There was a significant linear inverse relationship between HIF-1α protein level and infarct size ( r = −0.799, P < 0.01) among all groups. Furthermore, along with up-regulated HIF-1α expression, the levels of iNOS mRNA and protein were significantly increased in the PostC alone and DMOG plus PostC groups. In conclusion, these data suggest that HIF-1α is involved in cardioprotection by PostC and pharmacological augmentation of HIF-1α expression that enhances the infarct-sparing effect of PostC; iNOS, the downstream gene of HIF-1α, may participate in signaling pathways in mediating PostC’s protection. [ABSTRACT FROM AUTHOR]