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Cobalt Induces Hypoxia-Inducible Factor-1 Expression in Airway Smooth Muscle Cells by a Reactive Oxygen Species– and PI3K-Dependent Mechanism

Laboratory of Physiology and Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece

Address correspondence to: Efrosyni Paraskeva, Laboratory of Physiology, Department of Medicine, School of Health Sciences, University of Thessaly, Papakiriazi 22, 41222 Larissa, Greece. E-mail: fparaskeva{at}med.uth.gr

Cobalt can mimic hypoxia and has been implicated as a cause of lung defects. However, the effect of cobalt on airway smooth muscle (ASM) cells has not been analyzed in detail. In this article, we use primary cultures of ASM cells from rabbit trachea and show that exposure to cobalt chloride causes a rapid increase of the intracellular levels of hypoxia-inducible factor–1, which is detected predominantly inside the nucleus. With the use of specific inhibitors, we demonstrate that induction of hypoxia-inducible factor–1 by cobalt depends on active protein synthesis but not transcription. Furthermore, wortmannin, LY294002, and N-acetyl-L-cysteine inhibit the effect of cobalt, suggesting that it involves the phosphatidylinositol 3 kinase pathway and production of reactive oxygen species. Interestingly, cobalt chloride attenuates the contractile response of rabbit airways induced by potassium chloride, but not by acetylcholine, suggesting a link between the cellular response to hypoxic stimuli and the contractile properties of ASM cells.

Abbreviations: airway smooth muscle, ASM • acetylcholine, Ach • bovine serum albumin, BSA • cobalt chloride, CoCl₂ • enhanced version of the green fluorescent protein, GFP • hypoxia-inducible factor-1, HIF-1 • N-acetyl-L-cysteine, NAC • phosphatidylinositol 3-kinase, PI3K • reactive oxygen species, ROS • sodium dodecyl sulfate–polyacrylamide gel electrophoresis, SDS-PAGE • smooth muscle, SM • von Hippel-Lindau, VHL

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