Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1 alpha

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-1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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 +/- A 4.2% vs. 36 +/- A 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 +/- A 2.0% vs. 27 +/- A 4.2% in PostC alone, P < 0.05). There was a significant linear inverse relationship between HIF-1 alpha protein level and infarct size (r = -0.799, P < 0.01) among all groups. Furthermore, along with up-regulated HIF-1 alpha 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-1 alpha is involved in cardioprotection by PostC and pharmacological augmentation of HIF-1 alpha expression that enhances the infarct-sparing effect of PostC; iNOS, the downstream gene of HIF-1 alpha, may participate in signaling pathways in mediating PostC's protection.