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

Dimmeler, Stefanie; Fleming, Ingrid; Fisslthaler, Beate; Hermann, Corinna; Busse, Rudi; Zeiher, Andreas M.

doi:10.1038/21224

Cited by 3,591Nitric Oxide and Endothelin EffectsProtein Kinase Regulation and GTPase SignalingAngiogenesis and VEGF in Cancer

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

Dimmeler, Stefanie, Fleming, Ingrid, Fisslthaler, Beate, Hermann, Corinna, Busse, Rudi, Zeiher, Andreas M.·1999·Nature

DOI 10.1038/21224

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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 angiogenesis. 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 layer. Although shear-stress-mediated phosphorylation of eNOS is thought to regulate enzyme activity, the mechanism of activation of eNOS is not yet known. Here we demonstrate that the serine/threonine protein kinase Akt/PKB 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.

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Insulin induces NO-dependent vasodilation in skeletal muscle via stimulation of the insulin receptor, activation of IRS1, PI3-kinase, phosphorylation of Akt and subsequent phosphorylation of eNOS.
“Insulin induces nitric oxide (NO)-dependent vasodilation in skeletal muscle via stimulation of the insulin receptor, activation of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3 kinase (PI3-kinase), phosphorylation of Akt and subsequent phosphorylation of endothelial NOS (eNOS).”
From The Vasculature in Prediabetes (2018) · cites this paper as [40]

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Authors: Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., & Zeiher, A. M.
Affiliations: Goethe University Frankfurt (DE)
Corresponding author: Zeiher, Andreas M.
ORCID: Dimmeler, Stefanie
Fleming, Ingrid
Fisslthaler, Beate
Zeiher, Andreas M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1999-06
Volume: 399
Issue: 6736
Pages: 601-605
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/21224
OpenAlex: W1607892649
Cited by: 3,591
References: 32
Citations by year: 2026: 35 · 2025: 48 · 2024: 67 · 2023: 64 · 2022: 78 · 2021: 105 · 2020: 79 · 2019: 101 · 2018: 129 · 2017: 124 · 2016: 140 · 2015: 143 · 2014: 163 · 2013: 183 · 2012: 164
FWCI: 74.75
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: American Heart Association
National Institutes of Health
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: endothelial nitric oxide synthase, Akt, nitric oxide production, shear stress, endothelial cells, phosphatidylinositol 3-kinase, enzyme activation, cardiovascular homeostasis
MeSH terms: Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Binding Sites, Cell Line, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Humans, Nitric Oxide, Phosphorylation, Proto-Oncogene Proteins, Serine, Swine, Protein Serine-Threonine Kinases, Nitric Oxide Synthase, COS Cells, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III, In Vitro Techniques

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

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