Stabilization of hypoxia-inducible factor-1{alpha} by prostacyclin under prolonged hypoxia via reducing reactive oxygen species level in endothelial cells

• Published in: The Journal of biological chemistry Vol. 280; no. 44; p. 36567
• Main Authors: Chang, Tzu-Ching, Huang, Chung-Jen, Tam, Kabik, Chen, Su-Fen, Tan, Kien Thiam, Tsai, Ming-Song, Lin, Teng-Nan, Shyue, Song-Kun
• Format: Journal Article
• Language: English
• Published: United States 04.11.2005
• Subjects: Adenoviridae - genetics; Catalase - pharmacology; Cells, Cultured; Cyclooxygenase 1 - metabolism; Down-Regulation; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Epoprostenol - pharmacology; Humans; Hydrogen Peroxide - pharmacology; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; NADPH Oxidases - metabolism; Oxidants - pharmacology; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - metabolism; Prostaglandin-Endoperoxide Synthases - metabolism; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - metabolism; Reactive Oxygen Species - metabolism; Umbilical Veins - cytology; Umbilical Veins - drug effects; Umbilical Veins - metabolism
• ISSN: 0021-9258; 1083-351X

Hypoxia-inducible factor-1 (HIF-1) takes part in the transcriptional activation of hypoxia-responsive genes. HIF-1alpha, a subunit of HIF-1, is rapidly degraded under normoxic conditions by the ubiquitin-proteosome system. Hypoxia up-regulates HIF-1alpha by inhibiting its degradation, thereby allowing it to accumulate to high levels with 3-6 h of hypoxia treatment and decreasing thereafter. In vascular tissues, prostacyclin (prostaglandin I(2) (PGI(2))) is a potent vasodilator and inhibitor of platelet aggregation and is known as a vasoprotective molecule. However, the role of PGI(2) in HIF-1 activation has not been studied. In the present study, we investigated the effect of PGI(2) on HIF-1 regulation in human umbilical vein endothelial cells under prolonged hypoxia (12 h). Augmentation of PGI(2) via adenovirus-mediated gene transfer of both cyclooxygenase-1 and PGI(2) synthase activated HIF-1 by stabilizing HIF-1alpha in cells under prolonged hypoxia or the hypoxia-normoxia transition but not under normoxia. Exogenous H(2)O(2) abolished PGI(2)- and catalase-induced HIF-1alpha up-regulation, which suggests that degradation of HIF-1alpha under prolonged hypoxia is through a reactive oxygen species-dependent pathway. Moreover, PGI(2) attenuated NADPH oxidase activity by suppressing Rac1 and p47(phox) expression under hypoxia. These data demonstrate a novel function of PGI(2) in down-regulating reactive oxygen species production by attenuating NADPH oxidase activity, which stabilizes HIF-1alpha in human umbilical vein endothelial cells exposed to prolonged hypoxia.