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
- 1 February 2003
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 63 (2), 325-331
- https://doi.org/10.1124/mol.63.2.325
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 (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 (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.Keywords
This publication has 33 references indexed in Scilit:
- Specificity and mechanism of action of some commonly used protein kinase inhibitorsBiochemical Journal, 2000
- Mechanisms of Cerebral Arterial Relaxations to Hydrogen PeroxideStroke, 2000
- Phosphorylation and activation of the endothelial nitric oxide synthase by fluid shear stressActa Physiologica Scandinavica, 2000
- Hydrogen peroxide-induced endothelium-dependentGeneral Pharmacology: The Vascular System, 1999
- The Akt kinase signals directly to endothelial nitric oxide synthaseCurrent Biology, 1999
- AMP‐activated protein kinase phosphorylation of endothelial NO synthaseFEBS Letters, 1999
- Mediation of H2O2-induced vascular relaxation by endothelium-derived relaxing factorMolecular and Cellular Biochemistry, 1995
- Evidence suggesting that iron and calcium are interrelated in oxidant-induced DNA damageKidney International, 1993
- Hydrogen peroxide elicits activation of bovine pulmonary arterial soluble guanylate cyclase by a mechanism associated with its metabolism by catalaseBiochemical and Biophysical Research Communications, 1987
- Induction of vascular relaxation by hydroperoxidesBiochemical and Biophysical Research Communications, 1986