Advanced glycation end product-induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells

Angelika Bierhaus, Shlomit Chevion, Mordechai Chevion, Marion Hofmann, Peter Quehenberger, Thomas Illmer, Thomas Luther, Eduard Berentshtein, Hans Tritschler, Martin Müller, Peter Wahl, Reinhard Ziegler, Peter P. Nawroth*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

364 Scopus citations

Abstract

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-κB and thus promoted the upregulation of various NF- κB-controlled genes, including endothelial tissue factor. Supplementation of the cellular antioxidative defense with the natural occurring antioxidant α- 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-κB activation was also reduced in a time- and dose-dependent manner as long as α-lipoic acid was added at least 30 min before AGE albumin stimulation. Inhibition was not due to physical interactions with protein DNA binding, since α-lipoic acid, directly included into the binding reaction, did not prevent binding activity of recombinant NF-κB. Western blots further demonstrated that α-lipoic acid inhibited the release and translocation of NF-κB from the cytoplasm into the nucleus. As a consequence, α-lipoic acid reduced AGE albumin-induced NF-κB mediated transcription and expression of endothelial genes relevant in diabetes, such as tissue factor and endothelin- 1. Thus, supplementation of cellular antioxidative defense mechanisms by extracellularly administered α-lipoic acid reduces AGE albumin-induced endothelial dysfunction in vitro.

Original languageEnglish
Pages (from-to)1481-1490
Number of pages10
JournalDiabetes
Volume46
Issue number9
DOIs
StatePublished - Sep 1997

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