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

Atherosclerosis. 2006 Mar;185(1):70-7. doi: 10.1016/j.atherosclerosis.2005.06.013. Epub 2005 Aug 1.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Arteritis / etiology*
  • Arteritis / metabolism
  • Arteritis / prevention & control
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism
  • Atherosclerosis / prevention & control
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glycation End Products, Advanced / administration & dosage
  • Glycation End Products, Advanced / metabolism
  • Immunoblotting
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / administration & dosage*
  • Receptors, Immunologic / metabolism
  • Treatment Outcome
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Glycation End Products, Advanced
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Vascular Cell Adhesion Molecule-1