Rac1 and superoxide are required for the expression of cell adhesion molecules induced by tumor necrosis factor-alpha in endothelial cells

J Pharmacol Exp Ther. 2003 May;305(2):573-80. doi: 10.1124/jpet.102.047894. Epub 2003 Feb 11.


Oxidative signals play an important role in the regulation of endothelial cell adhesion molecule expression. Small GTP-binding protein Rac1 is activated by various proinflammatory substances and regulates superoxide generation in endothelial cells. In the present study, we demonstrate that adenoviral-mediated expression of dominant negative N17Rac1 (Ad.N17Rac1) suppresses tumor necrosis factor-alpha (TNF-alpha)-induced vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin gene expression in a dose-dependent manner. Ad.N17Rac1 did not inhibit TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB) binding activity or inhibitor of NF-kappaB-alpha degradation. In contrast, Ad.N17Rac1 inhibited TNF-alpha-induced NF-kappaB-driven HIV(kappaB)(4)-CAT and p288VCAM-Luc promoter activity, suggesting that N17Rac1 inhibits TNF-alpha-induced VCAM-1, E-selectin, and ICAM-1 through suppressing NF-kappaB-mediated transactivation. In addition, expression of superoxide dismutase by adenovirus suppressed TNF-alpha-induced VCAM-1, E-selectin, and ICAM-1 mRNA accumulation. However, adenoviral-mediated expression of catalase only partially inhibited TNF-alpha-induced E-selectin gene expression and had no effect on VCAM-1 and ICAM-1 gene expression. These data suggest that Rac1 and superoxide play crucial roles in the regulation of expression of cell adhesion molecules in endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Blotting, Northern
  • Catalase / biosynthesis
  • Cell Adhesion Molecules / biosynthesis*
  • Cell Adhesion Molecules / genetics
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytokines / biosynthesis
  • E-Selectin / biosynthesis
  • E-Selectin / genetics
  • Electrophoretic Mobility Shift Assay
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Genes, Reporter / genetics
  • Humans
  • Hydrogen Peroxide / metabolism
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • NF-kappa B / metabolism
  • Plasmids / genetics
  • RNA, Messenger / biosynthesis
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Stimulation, Chemical
  • Superoxide Dismutase / biosynthesis
  • Superoxides / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation / drug effects
  • Vascular Cell Adhesion Molecule-1 / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / genetics
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*


  • Cell Adhesion Molecules
  • Cytokines
  • E-Selectin
  • NF-kappa B
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Superoxides
  • Intercellular Adhesion Molecule-1
  • Hydrogen Peroxide
  • Catalase
  • Superoxide Dismutase
  • rac1 GTP-Binding Protein