title: Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells.
abstract: 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 kappaB (NF-kappaB) 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 IkappaB kinase activation, subsequent degradation of IkappaB, the cytoplasmic NF-kappaB inhibitor, and nuclear translocation of NF-kappaB. In contrast, TNF-alpha-induced NF-kappaB 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 IkappaB/NF-kappaB signaling pathway at the level, or upstream, of IkappaB kinase.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Frei
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D019040:E-Selectin; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D008063:Thioctic Acid; D005978:Glutathione; D001205:Ascorbic Acid