Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

Stefanie Dimmeler, Ingrid Fleming, Beate Fisslthaler, Corinna Hermann, Rudi Busse and Andreas M. Zeiher ()
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Stefanie Dimmeler: Molecular Cardiology
Ingrid Fleming: Institute of Cardiovascular Physiology, University of Frankfurt
Beate Fisslthaler: Institute of Cardiovascular Physiology, University of Frankfurt
Corinna Hermann: Molecular Cardiology
Rudi Busse: Institute of Cardiovascular Physiology, University of Frankfurt
Andreas M. Zeiher: Molecular Cardiology

Nature, 1999, vol. 399, issue 6736, 601-605

Abstract: Abstract Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is a fundamental determinant of cardiovascular homesotasis: it regulates systemic blood pressure, vascular remodelling and angiogenesis1,2,3. Physiologically, the most important stimulus for the continuous formation of NO is the viscous drag (shear stress) generated by the streaming blood on the endothelial layer4,5,6,7,8. Although shear-stress-mediated phosphorylation of eNOS is thought to regulate enzyme activity9,10, the mechanism of activation of eNOS is not yet known. Here we demonstrate that the serine/threonine protein kinase Akt/PKB11,12,13 mediates the activation of eNOS, leading to increased NO production. Inhibition of the phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS protein (at serine 1177) attenuates the serine phosphorylation and prevents the activation of eNOS. Mimicking the phosphorylation of Ser 1177 directly enhances enzyme activity and alters the sensitivity of the enzyme to Ca2+, rendering its activity maximal at sub-physiological concentrations of Ca2+. Thus, phosphorylation of eNOS by Akt represents a novel Ca2+-independent regulatory mechanism for activation of eNOS.

Date: 1999
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DOI: 10.1038/21224

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