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NF- κ B Independent Suppression of Endothelial Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 Gene Expression by Inhibition of Flavin Binding Proteins and Superoxide Production
Ist Teil von
Journal of molecular and cellular cardiology, 2000-08, Vol.32 (8), p.1499-1508
Ort / Verlag
England: Elsevier Ltd
Erscheinungsjahr
2000
Link zum Volltext
Quelle
EZB-NALI5-00465 Elsevier Archive NL
Beschreibungen/Notizen
Oxidation-reduction (redox) coupled mechanisms play an important role in the regulation of cell surface adhesion molecule expression. In endothelial cells membrane-bound NADH/NADPH oxidase is a significant source of intracellular superoxide (O2−) production. We explored the role of flavin containing proteins such as NADH/NADPH oxidase in the induction of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) gene expression in human aortic endothelial cells (HAECs) and human dermal microvascular endothelial cells (HMECs). Treatment of HAECs by tumor necrosis factor- α (TNF- α, 100 U/ml) for 1 h induced a 31% increase in O2−production within 5 min as determined by lucigenin chemiluminescence analysis of whole cells (n=4, P<0.05). Pretreatment with the NADH/NADPH oxidase inhibitor diphenylene iodonium (DPI, 40μ m) for 1 h inhibited O2−production. DPI also inhibited TNF and LPS-induced VCAM-1 and ICAM-1 cell surface expression and TNF- α, LPS, or IL-1 β induced VCAM-1 and ICAM-1 mRNA accumulation. However, DPI did not inhibit TNF- α -induced activation of nuclear NF- κ B-like binding activity in HAECs and HMECs. Furthermore, DPI did not inhibit TNF- α induced transactivation of NF- κ B-driven VCAM-1 and HIV-LTR promoter gene constructs in transiently transfected HMECs. These data suggest that flavin binding proteins such as NADH/NADPH oxidase can regulate VCAM-1 gene expression independent of NF- κ B. Furthermore, intracellular O2−generation is not necessary for NF- κ B activation or for transactivation of NF-κ B driven promoters.