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Molecular Pharmacology

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Research ArticleArticle

Akt-Dependent Phosphorylation of Serine 1179 and Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Cooperatively Mediate Activation of the Endothelial Nitric-Oxide Synthase by Hydrogen Peroxide

Hua Cai, Zongming Li, Michael E. Davis, William Kanner, David G. Harrison and Samuel C. Dudley Jr.
Molecular Pharmacology February 2003, 63 (2) 325-331; DOI: https://doi.org/10.1124/mol.63.2.325
Hua Cai
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Zongming Li
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Michael E. Davis
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William Kanner
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David G. Harrison
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Samuel C. Dudley Jr.
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Abstract

Hydrogen peroxide mediates vasodilation, but the mechanisms responsible for this process remain undefined. We examined the effect of H2O2 on nitric oxide (NO⋅) production and the signaling events involved. NO⋅ release from bovine aortic endothelial cells was detected with an NO⋅-specific microelectrode. The addition of H2O2 caused a potent dose-dependent increase in NO⋅ production. This was partially Ca2+-dependent because BAPTA/AM reduced NO⋅ production at low (<50 μM) but not high (>100 μM) concentrations of H2O2. Phosphatidylinositol (PI) 3-kinase inhibition [with wortmannin or 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], infection with a dominant-negative mutant of Akt, or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase ½ (MEK/ERK1/2) inhibition (with PD98059 or U0126) partially attenuated, whereas inhibition of both PI 3-kinase and MEK1/2 abolished H2O2-dependent NO⋅ production. ERK1/2 seemed necessary for NO⋅ production early (<5 min) after H2O2 addition, whereas PI 3-kinase/Akt was more important at later time points. Phosphorylation of endothelial nitric-oxide synthase (eNOS) at serine 1179 was observed >10 min after the addition of H2O2, and this was prevented by wortmannin but not by PD98059. c-Src family tyrosine kinase(s) was found to be upstream of H2O2-dependent Akt and eNOS serine 1179 phosphorylation and subsequent NO⋅ production. In summary, H2O2 causes endothelial NO⋅release mediated by cooperative effects between PI 3-kinase/Akt-dependent eNOS serine 1179 phosphorylation and activation of MEK/ERK1/2. This may represent an acute cellular adaptation to an increase in oxidant stress.

Footnotes

  • This study was supported by National Institutes of Health grants HL39006 (to D.G.H.), HL64828 (to S.C.D.), and HL59248 (to D.G.H.), National Institutes of Health Program Project grant 58000 (to D.G.H.), a Department of Veterans Affairs merit grant (to D.G.H.), a Procter & Gamble University Exploratory Research grant (to S.C.D.), a Scientist Development Award from the American Heart Association (to S.C.D.), and a Postdoctoral Fellowship Award from the American Heart Association (to H.C.).

  • This article was presented in part at the 74th Scientific Sessions of American Heart Association, Anaheim, CA, November 11–14, 2001.

  • Abbreviations:
    eNOS
    endothelial nitric-oxide synthase
    MEK
    mitogen-activated protein kinase kinase
    ERK1/2
    extracellular signal-regulated kinase 1/2
    PI
    phosphatidylinositol
    CaM kinase II
    calcium/calmodulin-dependent protein kinase II
    ERK5
    extracellular signal-regulated kinase 5
    AMPK
    AMP-dependent protein kinase
    BAPTA/AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid/acetoxymethyl ester
    LY294002
    2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
    PD98059
    2′-amino-3′-methoxyflavone
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene
    MOI
    multiplicity of infection
    PP1
    protein phosphatase 1
    • Received July 16, 2002.
    • Accepted October 28, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

Akt-Dependent Phosphorylation of Serine 1179 and Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Cooperatively Mediate Activation of the Endothelial Nitric-Oxide Synthase by Hydrogen Peroxide

Hua Cai, Zongming Li, Michael E. Davis, William Kanner, David G. Harrison and Samuel C. Dudley
Molecular Pharmacology February 1, 2003, 63 (2) 325-331; DOI: https://doi.org/10.1124/mol.63.2.325

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Research ArticleArticle

Akt-Dependent Phosphorylation of Serine 1179 and Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Cooperatively Mediate Activation of the Endothelial Nitric-Oxide Synthase by Hydrogen Peroxide

Hua Cai, Zongming Li, Michael E. Davis, William Kanner, David G. Harrison and Samuel C. Dudley
Molecular Pharmacology February 1, 2003, 63 (2) 325-331; DOI: https://doi.org/10.1124/mol.63.2.325
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