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Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding

S D Yan1, A M Schmidt, G M Anderson

  • 1Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.

The Journal of Biological Chemistry
|April 1, 1994
PubMed

Insights

Advanced glycation end products (AGEs) trigger cell damage through reactive oxygen species, contributing to vascular diseases. Blocking AGE interactions with receptors like RAGE and LF-L reduces this oxidant stress and potential lesion development.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Vascular Biology

Background:

  • Reactive oxygen intermediates are implicated in cell/tissue injury and vascular diseases.
  • Advanced glycation end products (AGEs), formed from glycated/oxidized proteins, generate oxygen-free radicals.
  • Cellular interactions with AGEs involve binding proteins like the receptor for AGE (RAGE) and lactoferrin-like polypeptide (LF-L).

Purpose of the Study:

  • To test the hypothesis that AGE ligands bound to RAGE and LF-L can induce cellular oxidant stress.
  • To investigate the role of AGEs in endothelial cell (EC) activation and vascular changes.
  • To explore potential therapeutic targets for AGE-induced vascular damage.

Main Methods:

  • Incubation of endothelial cells with AGE albumin or AGEs from diabetic plasma.
  • Measurement of thiobarbituric acid reactive substances (TBARS) and NF-kappa B activation.
  • In vivo studies involving infusion of AGE albumin into normal animals.
  • Assessment of malondialdehyde, TBARS, NF-kappa B activation, and heme oxygenase mRNA levels.
  • Inhibition studies using antibodies against AGE receptor/binding proteins and antioxidants.

Main Results:

  • AGEs induced EC oxidant stress, evidenced by increased TBARS and NF-kappa B activation.
  • These effects were blocked by antibodies to AGE receptor polypeptides and antioxidants.
  • In vivo, AGE albumin administration led to vessel wall damage markers and systemic oxidant stress.
  • AGE-induced oxidant stress and associated molecular changes were inhibited by pretreatment with antibodies or antioxidants.
  • Data suggest AGE interaction with cellular targets causes oxidant stress, affecting gene expression and cellular functions.

Conclusions:

  • The interaction of AGEs with cellular targets, such as endothelial cells, leads to oxidant stress.
  • This AGE-induced oxidant stress contributes to changes in gene expression and cellular properties.
  • These mechanisms may play a role in the development of vascular lesions in conditions like diabetes.
  • Further research is needed to determine the precise cellular locus (cell surface or intracellular) of AGE-induced oxidant stress.

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