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(The FASEB Journal. 2001;15:2423-2432.)
© 2001 FASEB

{alpha}-Lipoic acid inhibits TNF-{alpha}-induced NF-{kappa}B activation and adhesion molecule expression in human aortic endothelial cells

WEI-JIAN ZHANG and BALZ FREI1

Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA

1Correspondence: Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331, USA. E-mail: Balz.frei{at}orst.edu

Endothelial activation and monocyte adhesion are initiating steps in atherogenesis thought to be caused in part by oxidative stress. The metabolic thiol antioxidant {alpha}-lipoic acid has been suggested to be of therapeutic value in pathologies associated with redox imbalances. We investigated the role of (R)-{alpha}-lipoic acid (LA) vs. glutathione and ascorbic acid in tumor necrosis factor {alpha} (TNF-{alpha}) -induced adhesion molecule expression and nuclear factor {kappa}B (NF-{kappa}B) signaling in human aortic endothelial cells (HAEC). Preincubation of HAEC for 48 h with LA (0.05–1 mmol/l) dose-dependently inhibited TNF-{alpha} (10 U/ml) -induced adhesion of human monocytic THP-1 cells, as well as mRNA and protein expression of E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. LA also strongly inhibited TNF-{alpha}-induced mRNA expression of monocyte chemoattractant protein-1 but did not affect expression of TNF-{alpha} receptor 1. Furthermore, LA dose-dependently inhibited TNF-{alpha}-induced I{kappa}B kinase activation, subsequent degradation of I{kappa}B, the cytoplasmic NF-{kappa}B inhibitor, and nuclear translocation of NF-{kappa}B. In contrast, TNF-{alpha}-induced NF-{kappa}B activation and adhesion molecule expression were not affected by ascorbic acid or by manipulating cellular glutathione status with L-2-oxo-4-thiazolidinecarboxylic acid, N-acetyl-L-cysteine, or D,L-buthionine-S,R-sulfoximine. Our data show that clinically relevant concentrations of LA, but neither vitamin C nor glutathione, inhibit adhesion molecule expression in HAEC and monocyte adhesion by inhibiting the I{kappa}B/NF-{kappa}B signaling pathway at the level, or upstream, of I{kappa}B kinase.—Zhang, W.-J., Frei, B. {alpha}-Lipoic acid inhibits TNF-{alpha}-induced NF-{kappa}B activation and adhesion molecule expression in human aortic endothelial cells.


Key Words: antioxidants • adhesion molecules • endothelium • nuclear factor {kappa}B




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