Changes of hypoxia inducible factor 1 alpha and heme oxygenase 1 in the process of hypoxic pulmonary hypertension development in rats

AIM: To observe the expression of hypoxia inducible factor-1α (HIF-1α) gene and heme oxygenase-1 (HO-1) gene in pulmonary arteries in hypoxic rats. METHODS: Forty male Wistar rats were exposed to hypoxia for 0, 3, 7, 14 or 21 days. Mean pulmonary pressure (mPAP), vessel morphometry, right ventricle hypertrophy index (RVHI) were measured. Lungs were either inflation fixed for immunohistochemistry and in situ hybridization or frozen for later measurement of HO-1 enzyme activity. RESULTS: During hypoxia, mPAP increased to significantly higher values than the control values after 7-day of hypoxia，reaching its peak after 14-day of hypoxia, then remained on the high level. Pulmonary artery remodeling developed significantly after 14-day of hypoxia. Expression of HIF-1α protein in control was poorly positive, but was up-regulated in pulmonary arterial tunica intimae of all hypoxic rats. In pulmonary arterial tunica media, the levels of HIF-1α protein were markedly up-regulated after 3-day and 7-day of hypoxia, then tended to decline after 14-day and 21-day of hypoxia. HIF-1α mRNA staining was poorly positive in control, hypoxia for 3 days and hypoxia for 7 days, but began to enhance significantly after 14-day of hypoxia, then remained stable. Expression of HO-1 protein began to increase after 7-day of hypoxia, reaching its peak after 14-day of hypoxia, then remained stable. Expression of HO-1 mRNA began to increase after 3-day of hypoxia, reaching its peak after 7-day of hypoxia, then declined. CONCLUSION: HIF-1α and HO-1 are both involved in the pathogenesis of hypoxia-induced pulmonary hypertension in rats. Furthermore, HIF-1α may inter-regulate with HO-1 gene in this process.