Istituto di Fisiologia Clinica     
Lazzerini G., Del Turco S., Basta G., O'Loghlen A., Zampolli A., De Caterina R. Prominent role of NF-κ kappaB in the induction of endothelial activation by endogenous nitric oxide inhibition. In: Nitric Oxide-Biology and Chemistry, vol. 21 pp. 184 - 191. Elsevier, 2009.
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)-1α alpha, 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-1a 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-1α alpha (0.05-0.5 ng/mL), these determined a higher VCAM-1 expression than in the presence of L-NMMA or IL-1α alpha alone. Northern analysis indicated that VCAM-1 mRNA was induced by L-NMMA alone, and that the effects of L-NMMA and IL-1α alpha were, again, at least additive. Nuclear factor-κ kappaB (NF-κ 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-1α alpha only occurred for NF-κ 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-κ kappaB in the presence or absence of other inflammatory mediators.
URL: http://www.elsevier.com/locate/yniox
DOI: 10.1016/j.niox.2009.07.007
Subject Nitric oxide
Endothelial activation
Adhesion Molecules
Nuclear factor-kB

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