Lipopolysaccharide activates Akt in vascular smooth muscle cells resulting in induction of inducible nitric oxide synthase through nuclear factor-kappa B activation.

Abstract:

:Bacterial lipopolysaccharide and other immunostimulants induce gene expression of an isoform of nitric oxide synthase (iNOS) in vascular smooth muscle cells. This process is dependent on nuclear factor-kappa B (NF-kappa B) activation. The aim of this study was to investigate whether the NF-kappa B and Akt signaling pathways converge to induce iNOS in lipopolysaccharide-stimulated vascular smooth muscle cells. Treatment of vascular smooth muscle cells with lipopolysaccharide plus interferon-gamma (LPS/IFN) caused activation of Akt and NF-kappa B. LPS/IFN caused activation of the iNOS promoter and transcription of iNOS mRNA/protein, resulting in NO production. A pharmacological inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt pathway, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), inhibited phosphorylation of Akt and suppressed activation of NF-kappa B by attenuating the phosphorylation and degradation of I kappa B. LY294002 thereby inhibited LPS/IFN-induced iNOS expression and NO production. Another inhibitor of the PI3K-Akt pathway, wortmannin, also inhibited NO production in VSMC. LY294002 similarly inhibited interleukin-1 beta- or tumor necrosis factor-alpha-induced NO production. The data indicate that lipopolysaccharide or cytokine stimulation of vascular smooth muscle cells leads to activation of the PI3K-Akt pathway, which then activates the NF-kappa B pathway. Thus, the PI3K-Akt pathway controls the expression of iNOS in lipopolysaccharide- and cytokine-stimulated vascular smooth muscle cells.

journal_name

Eur J Pharmacol

authors

Hattori Y,Hattori S,Kasai K

doi

10.1016/j.ejphar.2003.09.034

keywords:

subject

Has Abstract

pub_date

2003-11-28 00:00:00

pages

153-8

issue

2-3

eissn

0014-2999

issn

1879-0712

pii

S0014299903024300

journal_volume

481

pub_type

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