Atherosclerosis 185 (2006) 70–77 RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes Thoralf Wendt a , Evis Harja a , Loredana Bucciarelli a , Wu Qu a , Yan Lu a , Ling Ling Rong a , Daniel G. Jenkins a , Guenther Stein b , Ann Marie Schmidt a , Shi Fang Yan a,∗ a Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W, 168th Street, Black Building 1705, New York, NY 10032, USA b Department of Internal Medicine IV, University of Jena, Jena, Germany Received 11 January 2005; accepted 1 June 2005 Available online 1 August 2005 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. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: RAGE; Atherosclerosis; Hyperglycemia; Type 2 diabetes 1. Introduction Extensive evidence from epidemiologic studies suggests that diabetes accelerates atherosclerosis and the incidence of heart attacks and strokes in human subjects [1]. To dissect the underlying mechanisms, animal models have been employed to delineate pathways contributing to accelerated initiation and progression of atherosclerosis, and to test potential targets for therapeutic intervention. Our work has focused on testing the contribution of the ∗ Corresponding author. Tel.: +1 212 305 6030; fax: +1 212 305 5337. E-mail address: sy18@columbia.edu (S.F. Yan). Receptor for Advanced Glycation Endproducts (RAGE), a member of the immunoglobulin superfamily of cell surface molecules, in diabetes-associated complications. Studies have demonstrated that a key property of this receptor is its ability to interact with distinct classes of ligands. Our first studies linked RAGE to engagement of Advanced Glycation Endproducts (AGEs) [2]. Driven by hyperglycemia, oxidant stress and inflammation, proteins and lipids may undergo non-enzymatic glycation and oxidation, thereby generat- ing new species distinct from the backbone protein/lipid structure. Such species impart a new signature in the vasculature; via RAGE, these molecules activate signaling mechanisms that upregulate proinflammatory pathways. 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.06.013