Advanced Glycation End Product-Induced Activation of NF-κB is Suppressed by α-Lipoic Acid in Cultured Endothelial Cells

作者：Angelika Bierhaus, Shlomit Chevion, Mordechai Chevion, Marion A. Hofmann, Peter Quehenberger, Thomas Illmer, Thomas Luther, Eduard Berentshtein, Hans Tritschler, Martin N. Muller, Peter M. Wahl, Reinhard Ziegler, Peter P. Nawroth · 发表于：Diabetes · 年份：1997 · DOI：10.2337/diab.46.9.1481 · 被引用次数：373 · 研究领域：Advanced Glycation End Products research、Biochemical Acid Research Studies、Microbial metabolism and enzyme function

Depletion of cellular antioxidant defense mechanisms and the generation of oxygen free radicals by advanced glycation end products (AGEs) have been proposed to play a major role in the pathogenesis of diabetic vascular complications. Here we demonstrate that incubation of cultured bovine aortic endothelial cells (BAECs) with AGE albumin (500 nmol/l) resulted in the impairment of reduced glutathione (GSH) and ascorbic acid levels. As a consequence, increased cellular oxidative stress led to the activation of the transcription factor NF-kappaB and thus promoted the upregulation of various NF-kappaB-controlled genes, including endothelial tissue factor. Supplementation of the cellular antioxidative defense with the natural occurring antioxidant alpha-lipoic acid before AGE albumin induction completely prevented the AGE albumin-dependent depletion of reduced glutathione and ascorbic acid. Electrophoretic mobility shift assays (EMSAs) revealed that AGE albumin-mediated NF-kappaB activation was also reduced in a time- and dose-dependent manner as long as alpha-lipoic acid was added at least 30 min before AGE albumin stimulation. Inhibition was not due to physical interactions with protein DNA binding, since alpha-lipoic acid, directly included into the binding reaction, did not prevent binding activity of recombinant NF-kappaB. Western blots further demonstrated that alpha-lipoic acid inhibited the release and translocation of NF-kappaB from the cytoplasm into the nucleus. As a con...