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

Author

Listed:
  • David Fulton

    (Boyer Center for Molecular Medicine, Yale University School of Medicine)

  • Jean-Philippe Gratton

    (Boyer Center for Molecular Medicine, Yale University School of Medicine)

  • Timothy J. McCabe

    (Boyer Center for Molecular Medicine, Yale University School of Medicine)

  • Jason Fontana

    (Boyer Center for Molecular Medicine, Yale University School of Medicine)

  • Yasushi Fujio

    (Cardiovascular Research, St. Elizabeth's Medical Center)

  • Kenneth Walsh

    (Cardiovascular Research, St. Elizabeth's Medical Center)

  • Thomas F. Franke

    (Columbia University)

  • Andreas Papapetropoulos

    (Boyer Center for Molecular Medicine, Yale University School of Medicine)

  • William C. Sessa

    (Boyer Center for Molecular Medicine, Yale University School of Medicine)

Abstract

Endothelial nitric oxide synthase (eNOS) is the nitric oxide synthase isoform responsible for maintaining systemic blood pressure, vascular remodelling and angiogenesis1,2,3,4. eNOS is phosphorylated in response to various forms of cellular stimulation5,6,7 but the role of phosphorylation in the regulation of nitric oxide (NO) production and the kinase(s) responsible are not 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-mediated gene transfer, activated Akt increases basal NO release from endothelial cells, and activation-deficient Akt attenuates NO production stimulated by vascular endothelial growth factor. Thus, eNOS is a newly described Akt substrate linking signal transduction by Akt to the release of the gaseous second messenger NO.

Suggested Citation

  • David Fulton & Jean-Philippe Gratton & Timothy J. McCabe & Jason Fontana & Yasushi Fujio & Kenneth Walsh & Thomas F. Franke & Andreas Papapetropoulos & William C. Sessa, 1999. "Regulation of endothelium-derived nitric oxide production by the protein kinase Akt," Nature, Nature, vol. 399(6736), pages 597-601, June.
    • Handle: RePEc:nat:nature:v:399:y:1999:i:6736:d:10.1038_21218
    DOI: 10.1038/21218
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    Cited by:

    1. Roberta d'Emmanuele di Villa Bianca & Emma Mitidieri & Ferdinando Fusco & Elena D'Aiuto & Paolo Grieco & Ettore Novellino & Ciro Imbimbo & Vincenzo Mirone & Giuseppe Cirino & Raffaella Sorrentino, 2012. "Endogenous Urotensin II Selectively Modulates Erectile Function through eNOS," PLOS ONE, Public Library of Science, vol. 7(2), pages 1-6, February.

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