Hypoxia-inducible factor 1 alpha upregulates the expression of inducible nitric oxide synthase gene in pulmonary arteries of hyposic rat.

OBJECTIVE: To investigate the expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and inducible nitric oxide synthase (iNOS) genes in rats' pulmonary arteries in different phases of hypoxia-induced pulmonary hypertension development.
METHODS: Models of chronic hypoxic pulmonary hypertension rat were duplicated by intermittent hypoxia. Mean pulmonary arterial pressure (mPAP) was measured by right-heart catheterization. HIF-1alpha and iNOS messenger ribonucleic acid (mRNA) were detected by in situ hybridization. HIF-1alpha and iNOS protein were measured by immunohistochemical analysis.
RESULTS: Expression of HIF-1alpha protein was upregulated in pulmonary arterial tunica intimae of all hypoxic rats. In pulmonary arterial tunica media, the level of HIF-1alpha protein was markedly upregulated at days 3 and 7 of hypoxia (P < 0.01), then tended to restore at 14 days and 21 days. HIF-1alpha mRNA levels in pulmonary arteries of rats began to increase significantly at day 14 of hypoxia (P < 0.01). Expression of iNOS mRNA and protein in pulmonary arteries of rats were upregulated by hypoxia for 3 days (P < 0.01), then reached its peak and maitained the same level while the extension of hypoxia. Linear correlation analysis showed that iNOS protein was associated with both mean pulmonary arterial pressure (r = 0.74, P < 0.01) and hypoxic pulmonary vascular remodeling (r = 0.78, P < 0.01), whereas the inverse was associated with HIF-1alpha protein (r = -0.52, P < 0.01).
CONCLUSIONS: HIF-1alpha and iNOS are both involved in the pathogenesis of hypoxia-induced pulmonary hypertension in rat. HIF-1alpha protein may upregulate the expression of iNOS gene by transcriptional activation; in addition, iNOS protein may inhibit the expression of HIF-1alpha protein.