RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice

• Published in: Circulation (New York, N.Y.) Vol. 106; no. 22; pp. 2827 - 2835
• Main Authors: BUCCIARELLI, Loredana G, WENDT, Thoralf, KASHYAP, Yogita, STERN, David M, SCHMIDT, Ann Marie, WU QU, YAN LU, LALLA, Evanthia, LING LING RONG, GOOVA, Mouza T, MOSER, Bernhard, KISLINGER, Thomas, LEE, Daniel C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 26.11.2002
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis - complications; Arteriosclerosis - drug therapy; Arteriosclerosis - pathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Count; Cell Division - drug effects; Cell Movement - drug effects; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Disease Models, Animal; Disease Progression; Injections, Intraperitoneal; Leukocytes, Mononuclear - pathology; Male; Medical sciences; Mice; Mice, Knockout; Muscle, Smooth, Vascular - pathology; Myocardium - pathology; Phagocytes - pathology; Receptor for Advanced Glycation End Products; Receptors, Immunologic - administration & dosage; Receptors, Immunologic - antagonists & inhibitors; Sinus of Valsalva - drug effects; Sinus of Valsalva - pathology; Streptozocin; Treatment Outcome; Vasculitis - complications; Vasculitis - drug therapy; Vasculitis - pathology; Endocrinopathy; muscle, smooth; Pathogenesis; Diabetes mellitus; Rodentia; Clinical form; Cardiovascular disease; Smooth muscle; Inflammation; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; Blood vessel; Atherosclerosis
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000039325.03698.36

Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice. Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed. RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.