Temporal and spatial expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in a rat model of myocardial ischemia with or without reperfusion.

Abstract

BACKGROUND AND PURPOSE: Although hypoxia-inducible factor-1alpha (HIF-1alpha) plays a major role in the prevention of myocardial ischemia, the temporal and spatial patterns of expression of HIF-1alpha in myocardial ischemia-reperfusion are not well known. This study examined the role of HIF-1alpha and vascular endothelial growth factor (VEGF) in myocardial ischemia-reperfusion. METHODS: Adult Wistar rats were studied after ligation of the left anterior descending coronary artery (LAD) for 30 min and then after reperfusion. HIF-1alpha and VEGF were measured immediately after relief of occlusion and at 30 min, 1, 3, 6, and 24 h after reperfusion. HIF-1alpha and VEGF proteins were also measured 6 h after permanent occlusion of the LAD. RESULTS: HIF-1alpha and VEGF mRNA increased 1.8- and 1.4-fold, respectively, immediately after relief of occlusion and reached a maximum of 4.3- and 2.3-fold, respectively, at 3 h after reperfusion and remained elevated up to 24 h. HIF-1alpha and VEGF proteins increased immediately after relief of ischemia. HIF-1alpha protein significantly increased from 0.5 h to 24 h after reperfusion and VEGF protein significantly increased from 1 h to 6 h after reperfusion compared to the sham control. Administration of HIF-1alpha antisense oligonucleotide before ligation of the LAD significantly inhibited VEGF protein expression induced by ischemia-reperfusion. Immunohistochemical study showed increased immunoreactivity of HIF-1alpha and VEGF in the jeopardized myocardium after ischemia-reperfusion. HIF-1alpha and VEGF proteins were increased at 6 h after permanent occlusion of the LAD. CONCLUSIONS: This study demonstrated that HIF-1alpha and VEGF were co-induced in a temporal and spatial pattern after ischemia-reperfusion in the rat ventricular myocardium.