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Research ArticleCELLULAR AND MOLECULAR

Rac1 and Superoxide Are Required for the Expression of Cell Adhesion Molecules Induced by Tumor Necrosis Factor-α in Endothelial Cells

Xi-Lin Chen, Qiang Zhang, Ruozhi Zhao, Xiaoyu Ding, Pradyumna E. Tummala and Russell M. Medford
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 573-580; DOI: https://doi.org/10.1124/jpet.102.047894
Xi-Lin Chen
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Qiang Zhang
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Ruozhi Zhao
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Xiaoyu Ding
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Pradyumna E. Tummala
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Russell M. Medford
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Abstract

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-α (TNF-α)-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-α-induced activation of nuclear factor-κB (NF-κB) binding activity or inhibitor of NF-κB-α degradation. In contrast, Ad.N17Rac1 inhibited TNF-α-induced NF-κB-driven HIV(κB)4-CAT and p288VCAM-Luc promoter activity, suggesting that N17Rac1 inhibits TNF-α-induced VCAM-1, E-selectin, and ICAM-1 through suppressing NF-κB-mediated transactivation. In addition, expression of superoxide dismutase by adenovirus suppressed TNF-α-induced VCAM-1, E-selectin, and ICAM-1 mRNA accumulation. However, adenoviral-mediated expression of catalase only partially inhibited TNF-α-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.

Footnotes

  • This study was supported by the National Institutes of Health Research Grant R01-HL-60135 (to X.C.), American Heart Association Grant-in-Aid (to X.C.), and by an unrestricted research grant from AtheroGenics, Inc. (to R.M.M.).

  • DOI: 10.1124/jpet.102.047894

  • Abbreviations:
    VCAM-1
    vascular cell adhesion molecule-1
    ICAM-1
    intercellular cell adhesion molecule-1
    TNF-α
    tumor necrosis factor-α
    NF-κB
    nuclear factor-κB
    IκB
    inhibitor of NF-κB
    MCP-1
    monocyte chemoattractant protein-1
    ROS
    reactive oxygen species
    IL
    interleukin
    HAECs
    human aortic endothelial cells
    HMECs
    human microvascular endothelial cells
    CAT
    chloramphenicol acetyltransferase
    ELISA
    enzyme-linked immunosorbent assay
    MOI
    multiplicity of infection
    Ad
    adenoviral
    SOD
    superoxide dismutase
    PI3K
    phosphatidylinositol 3-kinase
    HIV
    human immunodeficiency virus
    • Received December 10, 2002.
    • Accepted January 30, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleCELLULAR AND MOLECULAR

Rac1 and Superoxide Are Required for the Expression of Cell Adhesion Molecules Induced by Tumor Necrosis Factor-α in Endothelial Cells

Xi-Lin Chen, Qiang Zhang, Ruozhi Zhao, Xiaoyu Ding, Pradyumna E. Tummala and Russell M. Medford
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 573-580; DOI: https://doi.org/10.1124/jpet.102.047894

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Research ArticleCELLULAR AND MOLECULAR

Rac1 and Superoxide Are Required for the Expression of Cell Adhesion Molecules Induced by Tumor Necrosis Factor-α in Endothelial Cells

Xi-Lin Chen, Qiang Zhang, Ruozhi Zhao, Xiaoyu Ding, Pradyumna E. Tummala and Russell M. Medford
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 573-580; DOI: https://doi.org/10.1124/jpet.102.047894
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