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

Abstract

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-1alpha (HIF-1alpha) 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-1alpha 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-1alpha 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-1alpha protein level and infarct size (r = -0.799, P < 0.01) among all groups. Furthermore, along with up-regulated HIF-1alpha 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-1alpha is involved in cardioprotection by PostC and pharmacological augmentation of HIF-1alpha expression that enhances the infarct-sparing effect of PostC; iNOS, the downstream gene of HIF-1alpha, may participate in signaling pathways in mediating PostC's protection.

• Authors: Huan-Xin Zhao, Xiao-Liang Wang, Ye-Hong Wang, Ye Wu, Xiao-Yu Li, Xiao-Ping Lv, Zhi-Qing Zhao, Rong-Rui Zhao, Hui-Rong Liu
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 105 Issue 1 Pg. 109-18 (Jan 2010) ISSN: 1435-1803 [Electronic] Germany
• PMID: 19597757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids, Dicarboxylic
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• Procollagen-Proline Dioxygenase
• Nitric Oxide Synthase Type II
• Creatine Kinase
• Caspase 3
• oxalylglycine

Topics

• Amino Acids, Dicarboxylic
• Animals
• Apoptosis
• Caspase 3 (metabolism)
• Creatine Kinase (blood)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
• Myocardium (pathology)
• Nitric Oxide Synthase Type II (metabolism)
• Procollagen-Proline Dioxygenase (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction
• Up-Regulation