Advanced glycation end product receptor-1 transgenic mice are resistant to inflammation, oxidative stress, and post-injury intimal hyperplasia.
The high levels of oxidative stress (OS) and inflammation associated with cardiovascular disease are linked to pro-oxidants such as advanced glycation end products (AGEs). AGEs interact with multiple receptors, including receptor 1 (AGER1), which promotes AGE removal and blocks OS and inflammation, and RAGE, which enhances inflammation. In this study, we evaluated metabolic and vascular changes in AGER1 transgenic mice (AGER1-tg) subjected to an atherogenic diet and arterial wire-injury. Both baseline and postatherogenic diet serum and tissue AGEs as well as plasma 8-isoprostane levels were lower in AGER1-tg mice than in wild-type mice. The levels of injected (125)I-AGE in tissues were decreased as well in AGER1-tg mice. After ingesting a high-fat diet, AGER1-tg mice had a normal glucose tolerance and only 7% were hyperglycemic, whereas 53% of wild-type mice had stable hyperglycemia. After wire-injury, intimal lesions in AGER1-tg mice were small, whereas wild-type mice had diffuse intimal hyperplasia, a high intima/media ratio, and inflammatory cell infiltrates. In addition, AGER1 staining, prominent in AGER1-tg mice, was attenuated in 30 to 40% of wild-type cells, although all cells were strongly positive for AGEs. Thus, AGER1 overexpression in mice reduces basal levels of AGEs and OS, enhances resistance to diet-induced hyperglycemia and OS, and protects against injury-induced arterial intimal hyperplasia and inflammation, providing protection against OS and inflammation induced by AGEs and high-fat diets in vivo.
Division of Experimental Diabetes and Aging, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Massimo
M
Torreggiani
Huixian
H
Liu
Jin
J
Wu
Feng
F
Zheng
Weijing
W
Cai
Gary
G
Striker
Helen
H
Vlassara
D000818:Animals; D004032:Diet; D005263:Femoral Artery / Q000473:pathology; D018149:Glucose Intolerance / Q000150:complications; D017127:Glycation End Products, Advanced / Q000097:blood; D006965:Hyperplasia; D007249:Inflammation / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D018384:Oxidative Stress; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic