Hypoxia induces transforming growth factor-beta1 gene expression in the pulmonary artery of rats via hypoxia-inducible factor-1alpha.

The present study was undertaken to investigate the dynamic expression of hypoxia inducible factor-1alpha (HIF-1alpha) and transforming growth factor-beta1 (TGF-beta1) in hypoxia-induced pulmonary hypertension of rats. It was found that mean pulmonary arterial pressure (mPAP) increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d of hypoxia. HIF-1alpha mRNA staining was less positive in the control, hypoxia for 3 d and hypoxia for 7 d, but began to enhance significantly after 14 d of hypoxia, then remained stable. Expression of HIF-1alpha protein in the control was less positive, but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. TGF-beta1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, but showed no obvious changes after 3 or 7 d of hypoxia. In pulmonary tunica adventitia and tunica media, TGF-beta1 protein staining was less positive in control rats, but was markedly enhanced after 3 d of hypoxia, reaching its peak after 7 d of hypoxia, and then weakening after 14 and 21?d of hypoxia. Western blotting showed that HIF-1alpha protein levels increased significantly after 7 d of hypoxia and then remained at a high level. TGF-beta1 protein level was markedly enhanced after 3 d of hypoxia, reaching its peak after 7 d of hypoxia, and then decreasing after 14 and 21?d of hypoxia. Linear correlation analysis showed that HIF-1alpha mRNA, TGF-beta1 mRNA, TGF-beta1 protein were positively correlated with mPAP, vessel morphometry and right ventricular hypertrophy index. TGF-beta1 protein (tunica adventitia) was negatively correlated with HIF-1alpha mRNA. Taken together, our results suggest that changes in HIF-1alpha and TGF-beta1 expression after hypoxia play an important role in hypoxia-induced pulmonary hypertension of rats.