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 kappaB (NF-kappaB) activation may differ. The NO donors, but not 8-bromo-cGMP, decreased tumor necrosis factor alpha (TNF-alpha)-induced VCAM-1, ICAM-1, and E-selectin expression by 11-70%. In contrast, NAC completely abolished VCAM-1 and E-selectin expression and decreased ICAM-1 expression by 56%. Gel shift assays demonstrate that NF-kappaB activation was inhibited by both NO and antioxidants. The activation of NF-kappaB involves the phosphorylation and degradation of its cytoplasmic inhibitor IkappaB-alpha by 26S proteasomes. The 26S proteasome inhibitor MG132 prevented the degradation of phosphorylated IkappaB-alpha. NAC inhibited IkappaB kinase (IKK) activity and prevented IkappaB-alpha phosphorylation and degradation. In contrast, NO did not inhibit IKK activity, IkappaB-alpha phosphorylation, or IkappaB-alpha degradation. However, NO, but not antioxidants, induced IkappaB-alpha promoter activity. The inhibitory effects of NO on adhesion molecule expression, therefore, differs from that of antioxidants in terms of the mechanism by which NF-kappaB is inactivated.
Spiecker
M
M
Cardiovascular Division, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Darius
H
H
Kaboth
K
K
Hübner
F
F
Liao
J K
JK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D000975:Antioxidants; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D019040:E-Selectin; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse