Regulation of endothelium-derived nitric oxide production by the protein kinase Akt

Endothelial nitric oxide synthase (eNOS) is the nitric oxide synthase isofo rm responsible for maintaining systemic blood pressure, vascular remodellin g and angiogenesis(1-4), eNOS is phosphorylated in response to various form s of cellular stimulation(5-7), but the role of phosphorylation in the regu lation of nitric oxide (NO) production and the kinase(s) responsible are no t known. Here we show that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eNOS (S1179A) is resistant to phosphorylation and activation by Akt. Moreover, using adenovirus-media ted gene transfer, activated Akt increases basal NO release from endothelia l cells, and activation-deficient Akt attenuates NO production stimulated b y vascular endothelial growth factor. Thus, eNOS is a newly described Akt s ubstrate linking signal transduction by Akt to the release of the gaseous s econd messenger NO.