title: Deletion of bone marrow-derived receptor for advanced glycation end products inhibits atherosclerotic plaque progression.
abstract: BACKGROUND
  The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the inflammatory response in atherosclerosis. We sought to determine the role of bone marrow-derived RAGE in different stages of atherosclerotic development in apolipoprotein E-deficient mice (apoE(-/-)).
  
  
  METHODS
  Seven- and 23-week-old apoE(-/-) mice (n = 40) were lethally irradiated and given bone marrow from RAGE null (RAGE(-/-)/apoE(-/-)) or RAGE-bearing (RAGE(+/+)/apoE(-/-)) mice to apoE(-/-) mice to generate double knockout bone marrow chimera (RAGE(-/-)/apoE(-/-bmc) and RAGE(+/+)/apoE(-/-bmc)-, respectively). After 16 weeks on a standard chow diet, mice were sacrificed and atherosclerotic lesion formation was evaluated.
  
  
  RESULTS
  Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217,470 ± 17,480 μm(2) for the RAGE(-/-) /apoE(-/-bmc) mice compared to 244,764 ± 45,840 μm(2)), whereas lesions in the brachiocephalic arteries of the older RAGE(-/-)/apoE(-/-bmc) mice had significantly smaller lesions (94,049 ± 13,0844 μm(2) vs. 145,570 ± 11,488 μm(2), P < 0.05) as well as reduced average necrotic core area (48,600 ± 9220 μm(2) compared to 89,502 ± 10,032 μm(2), P < 0.05) when compared to RAGE(+/+)/apoE(-/-bmc) mice. Reduced plaque size and more stable plaque morphology was associated with significant reduced expression of VCAM-1, ICAM-1 and MCP-1. Accumulation of the RAGE ligand HMGB-1 was also significantly reduced within the lesions of RAGE(-/-)/apoE(-/-bmc) mice.
  
  
  CONCLUSIONS
  This study demonstrates that bone marrow-derived RAGE is an important factor in the progression of atherosclerotic plaques.
authors.affiliation: Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Morris-Rosenfeld
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
authors.forename: Michael R
authors.initials: MR
authors.lastname: Preusch
authors.forename: Claudia
authors.initials: C
authors.lastname: Albrecht
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Martin
authors.initials: M
authors.lastname: Andrassy
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rosenfeld
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Florian
authors.initials: F
authors.lastname: Bea
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D001853:Bone Marrow / Q000276:immunology; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1