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

• Published in: Atherosclerosis Vol. 185; no. 1; pp. 70 - 77
• Main Authors: Wendt, Thoralf, Harja, Evis, Bucciarelli, Loredana, Qu, Wu, Lu, Yan, Rong, Ling Ling, Jenkins, Daniel G., Stein, Guenther, Schmidt, Ann Marie, Yan, Shi Fang
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01-03-2006; Elsevier
• Subjects: Animals; Aorta, Thoracic - metabolism; Aorta, Thoracic - pathology; Arteritis - etiology; Arteritis - metabolism; Arteritis - prevention & control; Associated diseases and complications; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Glycation End Products, Advanced - administration & dosage; Glycation End Products, Advanced - metabolism; Hyperglycemia; Immunoblotting; Male; Management. Various non-drug treatments. Langerhans islet grafts; Medical sciences; Mice; Mice, Inbred C57BL; RAGE; Receptor for Advanced Glycation End Products; Receptors, Immunologic - administration & dosage; Receptors, Immunologic - metabolism; Treatment Outcome; Type 2 diabetes; Vascular Cell Adhesion Molecule-1 - metabolism; Type 2 diabetes; Hyperglycemia; RAGE; Atherosclerosis; Endocrinopathy; Antineoplastic agent; Pancreatic hormone; Vascular cell adhesion molecule 1; Tissue factor; Metalloendopeptidases; Cardiovascular disease; Lipids; Glucose; Premises; Glycation; Vascular disease; Blood vessel; Aorta; Hyperlipemia; Dyslipemia; Streptozotocin; Nutritional status; Obesity; Enzyme; Rodentia; Nutrition disorder; Metabolic diseases; Inflammation; Insulin; Artery; Gelatinase B; Peptidases; Vertebrata; Antibiotic; Mammalia; Mouse; Animal; Hydrolases; Circulatory system; Glycemia
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2005.06.013

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.