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Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products

Nikolaus Marx1, Daniel Walcher, Nina Ivanova

  • 1Department of Internal Medicine II-Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. nikolaus.marx@medizin.uni-ulm.de

Diabetes
|September 28, 2004
PubMed

Insights

Thiazolidinediones (TZDs) reduce the expression of receptors for advanced glycation end products (RAGE) in human endothelial cells. This finding suggests TZDs may help prevent vascular dysfunction in diabetic patients.

Area of Science:

  • Vascular Biology
  • Endocrinology
  • Pharmacology

Background:

  • Advanced glycation end products (AGEs) promote atherosclerosis in diabetes by activating receptors for AGE (RAGE) in vascular cells.
  • Interruption of the AGE-RAGE pathway has shown promise in reducing atherosclerotic lesion development in animal models.
  • Targeting RAGE expression presents a potential strategy for managing vascular complications in diabetic individuals.

Purpose of the Study:

  • To investigate whether thiazolidinediones (TZDs), used to treat type 2 diabetes, can modulate endothelial RAGE expression.
  • To explore the underlying mechanisms by which TZDs might affect RAGE expression.
  • To assess the functional consequences of TZD-induced changes in RAGE expression on endothelial cell responses.

Main Methods:

  • Human endothelial cells were stimulated with TZDs (rosiglitazone, pioglitazone) with or without tumor necrosis factor-alpha.
  • RAGE cell surface, total protein, and mRNA expression levels were quantified.
  • Nuclear factor-kappaB (NF-kappaB) activation and its effect on the RAGE promoter were analyzed.
  • Monocyte chemoattractant protein-1 (MCP-1) expression was measured following AGE or beta-amyloid stimulation in TZD-pretreated cells.

Main Results:

  • TZDs significantly decreased basal and tumor necrosis factor-alpha-induced RAGE cell surface and total protein expression.
  • TZDs also reduced RAGE mRNA expression in endothelial cells.
  • The observed reduction in RAGE expression was linked to the inhibition of NF-kappaB activation at the RAGE promoter.
  • TZD pretreatment diminished AGE- and beta-amyloid-induced MCP-1 expression, indicating reduced endothelial cell inflammatory response.

Conclusions:

  • TZDs effectively reduce RAGE expression in human endothelial cells.
  • This reduction in RAGE expression limits endothelial cell susceptibility to pro-inflammatory effects mediated by AGEs.
  • These findings offer novel insights into how TZDs, beyond their metabolic actions, may mitigate vascular dysfunction in diabetes.

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