(03377) Hypoxia Inducible Factor-1 Alpha Correlates the Expression of Heme Oxygenase 1 Gene in Pulmonary Arteries of Rat with Hypoxia-induced Pulmonary Hypertension

Qi-Fang LI^&
and Ai-Guo DAI*
( Department of Respiratory Medicine, Geriatric Hospital of Hunan Province,
Changsha 410001, China )

Abstract To test the hypothesis
that hypoxia inducible factor-1 alpha (HIF-1α) 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-1α 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-1α 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-1a 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-1α mRNA, HO-1 protein and mPAP were
associated with pulmonary remodeling. HIF-1α protein (tunica intima) was conversely
correlated with HIF-1α mRNA (r=0.921,P<0.01), HO-1 protein was conversely correlated with HIF-1α protein (tunica intima) (r=0.821,
P<0.01). HIF-1α 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.

Key words hypoxia inducible
factor-1; heme oxygenase 1; anoxia; hypertension; lung; gene expression

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Received: September 12, 2003 Accepted: November 14, 2003
This work was supported by the grants from the National Science Foundation of
China (No. 30270581) and the Hunan Province Educational Committee Major Foundation
(No. 02A047)
^& Postgraduate Student, Nanhua University
^*Corresponding author: Tel, 86-731-4762793; E-mail, [email protected]