NITRIC-OXIDE REGULATES VASCULAR CELL-ADHESION MOLECULE-1 GENE-EXPRESSION AND REDOX-SENSITIVE TRANSCRIPTIONAL EVENTS IN HUMAN VASCULAR ENDOTHELIAL-CELLS
Bv. Khan et al., NITRIC-OXIDE REGULATES VASCULAR CELL-ADHESION MOLECULE-1 GENE-EXPRESSION AND REDOX-SENSITIVE TRANSCRIPTIONAL EVENTS IN HUMAN VASCULAR ENDOTHELIAL-CELLS, Proceedings of the National Academy of Sciences of the United Statesof America, 93(17), 1996, pp. 9114-9119
Decreased nitric oxide (NO) activity, the formation of reactive oxygen
species, and increased endothelial expression of the redox-sensitive
vascular cell adhesion molecule 1 (VCAM-1) gene in the vessel wall are
early and characteristic features of atherosclerosis, To explore whet
her these phenomena are functionally interrelated, we tested the hypot
hesis that redox-sensitive VCAM-1 gene expression is regulated by a NO
-sensitive mechanism, In early passaged human umbilical vein endotheli
al cells and human dermal microvascular endothelial cells, the NO dono
r diethylamine-NO (DETA-NO, 100 mu M) reduced VCAM-1 gene expression i
nduced by the cytokine tumor necrosis factor alpha (TNF-alpha, 100 uni
ts/ml) at the cell surface level by 65% and intracellular adhesion mol
ecule 1 (ICAM-1) gene expression by 35%. E-selectin gene expression wa
s not affected, No effect on expression of cell adhesion molecules was
observed with DETA alone, Moreover, DETA-NO suppressed TNF-alpha-indu
ced mRNA accumulation of VCAM-1 and TNF-alpha-mediated transcriptional
activation of the human VCAM-1 promoter, Conversely, treatment with N
-G-monomethgl-L-arginine (L-NMMA, 1 mM), an inhibitor of NO synthesis,
augmented cytokine induction of VCAM-1 and ICAM-1 mRNA accumulation,
By gel mobility shift analysis, DETA-NO inhibited TNF-alpha activation
of DNA binding protein activity to the VCAM-1 NF-kappa B like binding
sites, Peroxy-fatty acids such as 13-hydroperoxydodecanoeic acid (lin
oleyl hydroperoxide) may serve as an intracellular signal for NF-kappa
B activation, Using thin layer chromatography; DETA-NO (100 phl) supp
ressed formation of this metabolite, suggesting that DETA-NO modifies
the reactivity of oxygen intermediates in the vascular endothelium. Th
rough this mechanism, NO may function as an immunomodulator of the ves
sel wall and thus mediate inflammatory events involved in the pathogen
esis of atherosclerosis.