NITRIC-OXIDE DECREASES CYTOKINE-INDUCED ENDOTHELIAL ACTIVATION - NITRIC-OXIDE SELECTIVELY REDUCES ENDOTHELIAL EXPRESSION OF ADHESION MOLECULES AND PROINFLAMMATORY CYTOKINES

To test the hypothesis that nitric oxide (NO) limits endothelial activ ation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the induci ble expression of vascular cell adhesion molecule-1 (VCAM(-)1). In a c oncentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-s timulated VCAM-1 expression by 35-55% as determined by cell surface en zyme immunoassays and flow cytometry. This inhibition was paralleled b y reduced monocyte adhesion to endothelial monolayers in nonstatic ass ays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosi s factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreas ed the endothelial expression of other leukocyte adhesion molecules (E -selectin and to a lesser extent, intercellular adhesion molecule-1) a nd secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO p roduction by L-N-monomethyl-arginine also induced the expression of VC AM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter repo rter gene constructs, and electrophoretic mobility shift assays indica ted that NO represses VCAM-1 gene transcription, in part, by inhibitin g NF-kappa B. We propose that NO's ability to limit endothelial activa tion and inhibit monocyte adhesion may contribute to some of its antia therogenic and antiinflammatory properties within the vessel wall.