title: RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice.
abstract: OBJECTIVE
  Receptor for advanced glycation end products (RAGE) plays a pivotal role in the genesis of diabetic vascular diseases. To further explore the mechanisms underlying atherosclerosis under non-diabetic conditions, we examined the effect of RAGE deficiency on atherosclerosis in hyperlipidaemic mice.
  
  
  RESULTS
  RAGE-/- mice were crossed with low-density lipoprotein receptor-deficient (LDLr-/-) mice to generate the double knockout (DKO) mice. After feeding with high-fat diet for 12 weeks, aortic atherosclerotic lesions were analysed histologically in these mice. Although there were no differences in serum levels of glucose and known RAGE ligands between DKO and LDLr-/- mice, DKO mice exhibited a significant decrease in the size and macrophage content in atherosclerotic lesions compared with LDLr-/- mice. Expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the aorta was lower in DKO mice than in LDLr-/- mice. Fluorescence-based assays revealed that oxidative stress in the vessel wall was attenuated in DKO mice than in LDLr-/- mice. Cell culture experiments revealed that RAGE mediated oxidative LDL-induced activation of p42/44 mitogen-activated protein kinases and oxidative stress in macrophages.
  
  
  CONCLUSIONS
  Oxidative LDL may be a ligand of RAGE in the hyperlipidaemic state. RAGE inactivation inhibits the atherosclerosis through reducing oxLDL-induced pro-inflammatory responses and oxidative stress in hyperlipidaemia.
authors.affiliation: Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment (ICMRT), Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yasuda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Honjo
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D006949:Hyperlipidemias / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D008077:Lipoproteins, LDL; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1