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.
Hu
Ruicheng
R
Department of Respiratory Medicine, Third Affiliated Hospital, Nanhua University, Hengyang 421900, China.
Dai
Aiguo
A
Tan
Shuangxiang
S
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D006976:Hypertension, Pulmonary / Q000201:enzymology*; D000860:Hypoxia / Q000201:enzymology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D011651:Pulmonary Artery / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat