Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI3K pathway

Adaptation to hypoxic stress provokes activation of the hypoxia-inducible-f actor-1 (HIF-1) which mediates gene expression of, e.g., erythropoietin or vascular endothelial growth factor. Detailed information on signaling pathw ays that stabilize HIF-1 is missing, but reactive oxygen species degrade th e HIF-1 alpha subunit, whereas phosphorylation causes its stabilization. It was believed that hypoxia resembles the only HIP-I inducer but recent evid ence characterized other activators of HIP-I such as nitric oxide (NO). Her ein, we concentrated on NO-evoked HIP-I induction as a heretofore unappreci ated inflammatory response in association with massive NO formation. We dem onstrated that S-nitrosoglutathione induces HIF-1 alpha accumulation and co ncomitant DNA binding. The response was attenuated by the kinase inhibitor genistein and blockers of phosphatidylinositol 3-kinase such as Ly 294002 o r wortmannin. Whereas mitogen-activated protein kinases were not involved, we noticed phosphorylation/activation of Akt in correlation with HIF-1 alph a stabilization. NO appears to regulate HIF-1 alpha via the PI 3K/Akt pathw ay under normoxic conditions. (C) 2000 Academic Press.