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Prominent role of NF-kappaB in the induction of endothelial activation by endogenous nitric oxide inhibition.
- Source :
-
Nitric oxide : biology and chemistry [Nitric Oxide] 2009 Nov-Dec; Vol. 21 (3-4), pp. 184-91. Date of Electronic Publication: 2009 Aug 03. - Publication Year :
- 2009
-
Abstract
- Decreased endothelial nitric oxide (NO) production and increased expression of vascular cell adhesion molecule-1 (VCAM-1) are early features of atherosclerosis. We investigated the effects of suppressing endogenous NO production by the NO synthase inhibitor l-mono-methyl-arginine (L-NMMA), given alone or in combination with interleukin(IL)-1alpha, on VCAM-1 expression by human umbilical vein endothelial cells (HUVEC). VCAM-1 expression (by enzyme immunoassay), barely detectable at baseline, was significantly increased by L-NMMA (by no more than 20% over control compared with IL-1alpha induction). This was paralleled by an increase in U937 monocytoid cell adhesion. When HUVEC incubated with L-NMMA were stimulated with low concentrations of IL-1alpha (0.05-0.5ng/mL), these determined a higher VCAM-1 expression than in the presence of L-NMMA or IL-1alpha alone. Northern analysis indicated that VCAM-1 mRNA was induced by L-NMMA alone, and that the effects of L-NMMA and IL-1alpha were, again, at least additive. Nuclear factor-kappaB (NF-kappaB), GATA, activator protein-1 (AP-1) and interferon regulatory factor-1 (IRF-1), transcription factors all involved in VCAM-1 gene expression, were all activated at electrophoretic mobility shift assay and at chromatin immunoprecipitation assay by L-NMMA, but additive effects with the combined administration of L-NMMA and IL-1alpha only occurred for NF-kappaB. These results support the view that endogenous NO mantains a normal endothelial non-reactivity towards circulating monocytes, and that suppression of this endogenous brake for endothelial activation results in the activation of multiple transcription factors even in the absence of other endothelial activators, with a prominent role of NF-kappaB in the presence or absence of other inflammatory mediators.
- Subjects :
- Atherosclerosis genetics
Cells, Cultured
Electrophoretic Mobility Shift Assay
Endothelium, Vascular drug effects
Enzyme Inhibitors pharmacology
GATA Transcription Factors drug effects
GATA Transcription Factors metabolism
Gene Expression Regulation
Humans
Interferon Regulatory Factor-1 drug effects
Interferon Regulatory Factor-1 metabolism
Nitric Oxide antagonists & inhibitors
Nitric Oxide biosynthesis
Nitric Oxide Synthase antagonists & inhibitors
Promoter Regions, Genetic
Transcription Factor AP-1 drug effects
Transcription Factor AP-1 metabolism
Vascular Cell Adhesion Molecule-1 genetics
omega-N-Methylarginine pharmacology
Atherosclerosis metabolism
Endothelium, Vascular metabolism
NF-kappa B metabolism
Nitric Oxide physiology
Vascular Cell Adhesion Molecule-1 biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1089-8611
- Volume :
- 21
- Issue :
- 3-4
- Database :
- MEDLINE
- Journal :
- Nitric oxide : biology and chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19654051
- Full Text :
- https://doi.org/10.1016/j.niox.2009.07.007