DIFFERENTIAL REGULATION OF ENDOTHELIAL-CELL ADHESION MOLECULE EXPRESSION BY NITRIC-OXIDE DONORS AND ANTIOXIDANTS

Although nitric oxide (NO) and antioxidants inhibit adhesion molecule expression, their inhibitory effects on nuclear factor kappa B (NF-kap pa B) activation may differ. The NO donors, but not 8-bromo-cGMP, decr eased tumor necrosis factor alpha (TNF-alpha)-induced VCAM-1, ICAM-1, and E-selectin expression by 11-70%. In contrast, NAC completely aboli shed VCAM-1 and E-selectin expression and decreased ICAM-1 expression by 56%. Gel shift assays demonstrate that NF-kappa B activation was in hibited by both NO and antioxidants. The activation of NF-kappa B invo lves the phosphorylation and degradation of its cytoplasmic inhibitor I kappa B-alpha by 26S proteasomes. The 26S proteasome inhibitor MG132 prevented the degradation of phosphorylated I kappa B-alpha. NAC inhi bited I kappa B kinase (IKK) activity and prevented I kappa B-alpha ph osphorylation and degradation. In contrast, NO did not inhibit IKK act ivity, I kappa B-alpha phosphorylation, or I kappa B-alpha degradation . However, NO, but not antioxidants, induced I kappa B-alpha promoter activity. Tbe inhibitory effects of NO on adhesion molecule expression , therefore, differs from that of antioxidants in terms of the mechani sm by which NF-kappa B is inactivated.