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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 11, 2003; DOI: 10.1124/jpet.102.047894

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Vol. 305, Issue 2, 573-580, May 2003

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

Xi-Lin Chen , Qiang Zhang, Ruozhi Zhao, Xiaoyu Ding, Pradyumna E. Tummala and Russell M. Medford

Discovery Research, AtheroGenics, Inc., Alpharetta, Georgia (X.-L.C., R.M.M.); and Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia (X.-L.C., Q.Z., R.Z., X.D., P.E.T., R.M.M.)

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-kappa B (NF-kappa B) binding activity or inhibitor of NF-kappa B-alpha degradation. In contrast, Ad.N17Rac1 inhibited TNF-alpha -induced NF-kappa B-driven HIV(kappa B)4-CAT and p288VCAM-Luc promoter activity, suggesting that N17Rac1 inhibits TNF-alpha -induced VCAM-1, E-selectin, and ICAM-1 through suppressing NF-kappa B-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.

0022-3565/03/3052-0573$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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