title: Stabilization of hypoxia-inducible factor-1{alpha} by prostacyclin under prolonged hypoxia via reducing reactive oxygen species level in endothelial cells.
abstract: 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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Chang
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Huang
authors.forename: Kabik
authors.initials: K
authors.lastname: Tam
authors.forename: Su-Fen
authors.initials: SF
authors.lastname: Chen
authors.forename: Kien Thiam
authors.initials: KT
authors.lastname: Tan
authors.forename: Ming-Song
authors.initials: MS
authors.lastname: Tsai
authors.forename: Teng-Nan
authors.initials: TN
authors.lastname: Lin
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016877:Oxidants; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D011464:Epoprostenol; D002374:Catalase; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020830:rac1 GTP-Binding Protein