RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes

Thoralf Wendt, Evis Harja, Loredana Bucciarelli, Wu Qu, Yan Lu, Ling Ling Rong, Daniel G. Jenkins, Guenther Stein, Ann Marie Schmidt, Shi Fang Yan

Research output: Contribution to journalArticlepeer-review

Abstract

Previous studies demonstrated that induction of diabetes with streptozotocin (stz) accelerated atherosclerosis in hyperlipidemic apo E null (-/-) mice. Blockade of the Receptor for Advanced Glycation Endproducts (RAGE) in those animals suppressed acceleration of atherosclerotic lesion area, in a manner independent of changes in levels of glucose, insulin or lipids. In the present studies, we extended these concepts to a murine model of type 2 diabetes, and bred apo E -/- mice into the db/db background. Db/db mice are a model of obesity and insulin resistance-mediated hyperglycemia. Compared to apo E -/- m/db (non-diabetic) mice, apo E -/- db/db (diabetic) mice displayed accelerated atherosclerosis at the aortic sinus. Consistent with an important role for RAGE in this process, administration of soluble (s) RAGE, the extracellular ligand-binding domain of RAGE, resulted in significantly reduced atherosclerotic lesion area in a glycemia- and lipid-independent manner. In parallel, apo E -/- db/db mice displayed RAGE-dependent enhanced expression of Vascular Cell Adhesion Molecule-1, tissue factor and matrix metalloproteinase (MMP)-9 antigen/activity in aortae compared to non-diabetic animals. In addition, consistent with the premise that upregulation of RAGE ligands and RAGE occurs even in the non-diabetic, hyperlipidemic state, albeit to lesser degrees than in diabetes, administration of sRAGE to apo E -/- m/db mice resulted in decreased atherosclerotic lesion area at the aortic sinus. Taken together, these findings establish a new murine model for the study of atherosclerosis in type 2 diabetes and highlight important roles for RAGE in proatherogenic mechanisms in hyperglycemia triggered by insulin resistance.

Original languageEnglish
Pages (from-to)70-77
Number of pages8
JournalAtherosclerosis
Volume185
Issue number1
DOIs
Publication statusPublished - Mar 2006

Keywords

  • Atherosclerosis
  • Hyperglycemia
  • RAGE
  • Type 2 diabetes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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