NITRIC-OXIDE REGULATES VASCULAR CELL-ADHESION MOLECULE-1 GENE-EXPRESSION AND REDOX-SENSITIVE TRANSCRIPTIONAL EVENTS IN HUMAN VASCULAR ENDOTHELIAL-CELLS

Citation
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
Citations number
44
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
93
Issue
17
Year of publication
1996
Pages
9114 - 9119
Database
ISI
SICI code
0027-8424(1996)93:17<9114:NRVCMG>2.0.ZU;2-Q
Abstract
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.