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

Diabetes. 1997 Sep;46(9):1481-90. doi: 10.2337/diab.46.9.1481.


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 consequence, alpha-lipoic acid reduced AGE albumin-induced NF-kappaB 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 alpha-lipoic acid reduces AGE albumin-induced endothelial dysfunction in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology*
  • Ascorbic Acid / chemistry
  • Ascorbic Acid / metabolism
  • Cell Compartmentation / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / metabolism
  • Endothelium, Vascular / physiology*
  • Gene Expression Regulation / drug effects
  • Glutathione / metabolism
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • NF-kappa B / metabolism*
  • Oxidation-Reduction
  • Thioctic Acid / pharmacology*
  • Thromboplastin / genetics*


  • Antioxidants
  • DNA-Binding Proteins
  • Glycation End Products, Advanced
  • NF-kappa B
  • Thioctic Acid
  • Thromboplastin
  • Glutathione
  • Ascorbic Acid