Hypoxia inducible factor-1 alpha correlates the expression of heme oxygenase 1 gene in pulmonary arteries of rat with hypoxia-induced pulmonary hypertension.

To test the hypothesis that hypoxia inducible factor-1 alpha (HIF-1alpha) up-regulated the expression of heme oxygenase-1 (HO-1) gene in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension, 8 male Wistar rats in each of 5 groups were exposed to hypoxia for 0, 3, 7, 14 or 21 d, respectively. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index were measured. Lungs were inflation fixed for immunohistochemistry, in situ hybridization; frozen for later measurement of HO-1 enzyme activity. mPAP increased significantly after 7 d of hypoxia [(18.4 +/- 0.4) mmHg, P<0.05], reaching its peak after 14 d of hypoxia, then remained stable. Pulmonary artery remodeling became to develop significantly after 14 d of hypoxia. HIF-1alpha protein in control was poorly positive (0.05 +/- 0.01), but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterial tunica media, the levels of HIF-1alpha protein were markedly up-regulated after 3 d and 7 d of hypoxia (0.20 +/- 0.02; 0.22 +/- 0.02, P<0.05), then declined after 14 d and 21 d of hypoxia. HIF-1alpha mRNA staining was poorly positive in control, hypoxia for 3 and 7 d, but enhanced significantly after 14 d of hypoxia (0.20 +/- 0.02, P<0.05), then remained stable. HO-1 protein increased after 7 d of hypoxia (0.10 +/- 0.01, P<0.05), reaching its peak after 14 d of hypoxia (0.21 +/- 0.02, P<0.05), then remained stable. HO-1 mRNA increased after 3 d of hypoxia, reaching its peak after 7 d of hypoxia (0.17 +/- 0.01, P<0.05), then declined. Linear correlation analysis showed that HIF-1alpha mRNA, HO-1 protein and mPAP were associated with pulmonary remodeling. HIF-1alpha protein (tunica intima) was conversely correlated with HIF-1alpha mRNA (r=0.921,P<0.01), HO-1 protein was conversely correlated with HIF-1alpha protein (tunica intima) (r=0.821, P<0.01). HIF-1alpha and HO-1 were both involved in the pathogenesis of hypoxia-induced pulmonary hypertension in rat. Hypoxia inducible factor-1 alpha correlated the expression of heme oxygenase 1 gene in pulmonary arteries of rat with hypoxia-induced pulmonary hypertension.