Cited by 381Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressProtein Kinase Regulation and GTPase Signaling

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Hydrogen Peroxide Activates Endothelial Nitric-oxide Synthase through Coordinated Phosphorylation and Dephosphorylation via a Phosphoinositide 3-Kinase-dependent Signaling Pathway

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Thomas, Shane R., Chen, Kai, Keaney, John F.·2002·Journal of Biological Chemistry

DOI 10.1074/jbc.m109107200

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Abstract

Endothelial nitric-oxide synthase (eNOS) is an important component of vascular homeostasis. During vascular disease, endothelial cells are exposed to excess reactive oxygen species that can alter cellular phenotype by inducing various signaling pathways. In the current study, we examined the implications of H(2)O(2)-induced signaling for eNOS phosphorylation status and activity in porcine aortic endothelial cells. We found that H(2)O(2) treatment enhanced eNOS activity and NO bioactivity as determined by the conversion of l-[(3)H]arginine to l-[(3)H]citrulline and cellular cGMP content. Concomitant with eNOS activation, H(2)O(2) also activated Akt, increased eNOS phosphorylation at Ser-1177, and decreased eNOS phosphorylation at Thr-495. H(2)O(2)-induced promotion of eNOS activity and modulation of the eNOS phosphorylation status at Ser-1177 and Thr-495 were significantly attenuated by selective inhibitors of Src kinase, the ErbB receptor family, and phosphoinositide 3-kinase (PI 3-K). We found that Akt activation, eNOS Ser-1177 phosphorylation, and eNOS activation by H(2)O(2) were calcium-dependent, whereas eNOS dephosphorylation at Thr-495 was not, suggesting a branch point in the signaling cascade downstream from PI 3-K. Consistent with this, overexpression of a dominant negative isoform of Akt inhibited H(2)O(2)-induced phosphorylation of eNOS at Ser-1177 but not dephosphorylation of eNOS at Thr-495. Together, these data indicate that H(2)O(2) promotes calcium-dependent eNOS activity through a coordinated change in the phosphorylation status of the enzyme mediated by Src- and ErbB receptor-dependent PI 3-K activation. In turn, PI 3-K mediates eNOS Ser-1177 phosphorylation via a calcium- and Akt-dependent pathway, whereas eNOS Thr-495 dephosphorylation does not involve calcium or Akt. This response may represent an attempt by endothelial cells to maintain NO bioactivity under conditions of enhanced oxidative stress.

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Authors: Thomas, S. R., Chen, K., & Keaney, J. F.
Affiliations: Boston University (US)
Corresponding author: Keaney, John F.
ORCID: Thomas, Shane R.
Keaney, John F.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2002-02
Volume: 277
Issue: 8
Pages: 6017-6024
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m109107200
OpenAlex: W2119043221
Cited by: 381
References: 47
Citations by year: 2026: 2 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 10 · 2021: 12 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 14 · 2016: 13 · 2015: 20 · 2014: 21 · 2013: 17 · 2012: 19
FWCI: 16.21
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6836 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01dk055656-03)
National Heart, Lung, and Blood Institute (P01HL060886, HL-60886)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-55656)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: hydrogen peroxide, endothelial nitric oxide synthase, eNOS phosphorylation, phosphatidylinositol 3-kinase, Akt signaling, Src kinase, ErbB receptors, calcium signaling, nitric oxide bioactivity, cyclic GMP, reactive oxygen species
MeSH terms: Animals, Aorta, Arginine, Cells, Cultured, Chromones, Citrulline, Egtazic Acid, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Hydrogen Peroxide, Kinetics, Morpholines, Nitric Oxide, Phosphorylation, Phosphoserine, Phosphothreonine, Quinazolines, Swine, Signal Transduction, Nitric Oxide Synthase, Phosphatidylinositol 3-Kinases, Calcium Signaling, Tyrphostins, Nitric Oxide Synthase Type III

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Hydrogen Peroxide Activates Endothelial Nitric-oxide Synthase through Coordinated Phosphorylation and Dephosphorylation via a Phosphoinositide 3-Kinase-dependent Signaling Pathway

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