Thiazolidinediones Reduce Endothelial Expression of Receptors for Advanced Glycation End Products

  1. Nikolaus Marx1,
  2. Daniel Walcher1,
  3. Nina Ivanova1,
  4. Kirstin Rautzenberg1,
  5. Annelie Jung1,
  6. Reinhard Friedl2,
  7. Vinzenz Hombach1,
  8. Raffaele de Caterina3,
  9. Giuseppina Basta4,
  10. Marie-Paule Wautier5 and
  11. Jean-Luc Wautiers
  1. 1Department of Internal Medicine II–Cardiology, University of Ulm, Germany
  2. 2Department of Cardiac Surgery, University of Ulm, Germany
  3. 3University Cardiology Division, G. d’Annunzio University, Chieti, Italy
  4. 4Institute of Clinical Physiology, CNR Pisa, Italy
  5. 5Institut National de la Transfusion Sanguine, Paris, France
  1. Address correspondence and reprint requests to Nikolaus Marx, MD, Department of Internal Medicine II–Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-mail: nikolaus.marx{at}medizin.uni-ulm.de

Abstract

Advanced glycation end products (AGEs) are critically involved in atherogenesis in diabetes by binding to receptors for AGE (RAGEs) in vascular cells, thus inducing the expression of proinflammatory mediators. In animal models, interruption of the AGE-RAGE interaction reduces lesion size and plaque development. Therefore, limiting RAGE expression might be an intriguing concept to modulate vascular disease in diabetic patients. The present study investigated whether thiazolidinediones (TZDs), antidiabetic agents clinically used to treat patients with type 2 diabetes, might modulate endothelial RAGE expression. Stimulation of human endothelial cells with rosiglitazone or pioglitazone decreased basal as well as tumor necrosis factor-α–induced RAGE cell surface and total protein expression. In addition, TZDs reduced RAGE mRNA expression in endothelial cells. These effects on RAGE expression were caused by an inhibition of nuclear factor-κB (NF-κB) activation at the proximal NF-κB site of the RAGE promoter. The functional relevance of reduced RAGE expression was demonstrated by showing that pretreatment of endothelial cells with TZDs decreased AGE- as well as β-amyloid–induced monocyte chemoattractant protein-1 expression. In conclusion, TZDs reduce RAGE expression in human endothelial cells, thus limiting the cells’ susceptibility toward proinflammatory AGE effects. These data provide new insight on how TZDs, in addition to their metabolic effects, might modulate the development of vascular dysfunction in diabetic patients.

Footnotes

  • N.M. and D.W. contributed equally to this work.

    N.M. has received an unrestricted research grant from GlaxoSmithKline Germany and has received speaking engagements from GlaxoSmithKline and Takeda Pharmaceuticals.

    • Accepted July 15, 2004.
    • Received November 7, 2003.
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