Sandau K B, Faus H G, Brüne B
Faculty of Medicine, Department of Medicine IV, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Biochem Biophys Res Commun. 2000 Nov 11;278(1):263-7. doi: 10.1006/bbrc.2000.3789.
Adaptation to hypoxic stress provokes activation of the hypoxia-inducible-factor-1 (HIF-1) which mediates gene expression of, e.g., erythropoietin or vascular endothelial growth factor. Detailed information on signaling pathways that stabilize HIF-1 is missing, but reactive oxygen species degrade the HIF-1 alpha subunit, whereas phosphorylation causes its stabilization. It was believed that hypoxia resembles the only HIF-1 inducer but recent evidence characterized other activators of HIF-1 such as nitric oxide (NO). Herein, we concentrated on NO-evoked HIF-1 induction as a heretofore unappreciated inflammatory response in association with massive NO formation. We demonstrated that S-nitrosoglutathione induces HIF-1 alpha accumulation and concomitant DNA binding. The response was attenuated by the kinase inhibitor genistein and blockers of phosphatidylinositol 3-kinase such as Ly 294002 or wortmannin. Whereas mitogen-activated protein kinases were not involved, we noticed phosphorylation/activation of Akt in correlation with HIF-1 alpha stabilization. NO appears to regulate HIF-1 alpha via the PI 3K/Akt pathway under normoxic conditions.
对缺氧应激的适应会引发缺氧诱导因子-1（HIF-1）的激活，HIF-1可介导如促红细胞生成素或血管内皮生长因子等的基因表达。关于稳定HIF-1的信号通路的详细信息尚不清楚，但活性氧会降解HIF-1α亚基，而磷酸化则会使其稳定。人们曾认为缺氧是唯一的HIF-1诱导剂，但最近的证据表明了其他HIF-1激活剂，如一氧化氮（NO）。在此，我们专注于NO引发的HIF-1诱导，这是一种迄今为止未被重视的与大量NO形成相关的炎症反应。我们证明了S-亚硝基谷胱甘肽会诱导HIF-1α积累及伴随的DNA结合。该反应被激酶抑制剂染料木黄酮以及磷脂酰肌醇3激酶阻滞剂如Ly 294002或渥曼青霉素减弱。虽然丝裂原活化蛋白激酶未参与其中，但我们注意到Akt的磷酸化/激活与HIF-1α稳定相关。在常氧条件下，NO似乎通过PI 3K/Akt途径调节HIF-1α。
