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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

https://doi.org/10.1006/jmcc.2000.1183Get rights and content

Abstract

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 O2production 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 O2production. 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 O2generation is not necessary for NF- κ B activation or for transactivation of NF-κ B driven promoters.

References (44)

  • R Miesel et al.

    Suppression of inflammatory arthritis by simultaneous inhibition of nitric oxide synthase and NADPH oxidase

    Free Radic Biol Med

    (1996)
  • A Majander et al.

    DiphenylÍeneiodonium inhibits reduction of iron-sulfur clusters in the mitochondrial NADH-ubiquinone oxidoreductase (Complex I)

    J Biol Chem

    (1994)
  • RN Poston et al.

    Expression of intercellular adhesion molecule-1 in atherosclerotic plaques

    Am J Pathol

    (1992)
  • H Li et al.

    An atheroÍgenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium

    Arterio Thromb

    (1993)
  • MI Cybulsky et al.

    Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis

    Science

    (1991)
  • N Marui et al.

    Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells

    J Clin Invest

    (1993)
  • C Weber et al.

    Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-kappa B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals

    Arterio Thromb

    (1994)
  • G Voraberger et al.

    Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5′-regulatory region. Induction by cytokines and phorbol ester

    J Immunol

    (1991)
  • MS Wolin

    Reactive oxygen species and vascular signal transduction mechanisms

    Microcirculation

    (1996)
  • DE Agwu et al.

    Phosphatidic acid as a second messenger in human polymorphonuclear leukocytes. Effects on activation of NADPH oxidase

    J Clin Invest

    (1991)
  • S Parthasarathy et al.

    A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein

    Proc Natl Acad Sci USA

    (1989)
  • DJ Morre

    Hormone- and growth factor-stimulated NADH oxidase

    J Bioenerg Biomembr

    (1994)
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    Please address all correspondence to: Xi-Lin Chen MD, PhD, AtheroGenics, Inc8995 Westside Parkway, Alpharetta, GA 30004, USA.

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