title: Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice.
abstract: Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Reigh-Yi
authors.initials: RY
authors.lastname: Lin
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: John T
authors.initials: JT
authors.lastname: Fallon
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000139:chemically induced*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D017127:Glycation End Products, Advanced / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology / Q000378:metabolism; D006937:Hypercholesterolemia / Q000235:genetics; D006949:Hyperlipidemias / Q000209:etiology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D000939:Epitopes; D017127:Glycation End Products, Advanced