title: Insulin-degrading enzyme deficiency in bone marrow cells increases atherosclerosis in LDL receptor-deficient mice.
abstract: BACKGROUND
  Insulin-degrading enzyme (IDE), a protease implicated in several chronic diseases, associates with the cytoplasmic domain of the macrophage Type A scavenger receptor (SR-A). Our goal was to investigate the effect of IDE deficiency (Ide(-/-)) on diet-induced atherosclerosis in low density lipoprotein-deficient (Ldlr(-/-)) mice and on SR-A function.
  
  
  METHODS
  Irradiated Ldlr(-/-) or Ide(-/-)Ldlr(-/-) mice were reconstituted with wild-type or Ide(-/-) bone marrow and, 6 weeks later, were placed on a high-fat diet for 8 weeks.
  
  
  RESULTS
  After 8 weeks on a high-fat diet, male Ldlr(-/-) recipients of Ide(-/-) bone marrow had more atherosclerosis, higher serum cholesterol and increased lesion-associated β-amyloid, an IDE substrate, and receptor for advanced glycation end products (RAGE), a proinflammatory receptor for β-amyloid, compared to male Ldlr(-/-) recipients of wild-type bone marrow. IDE deficiency in male Ldlr(-/-) recipient mice did not affect atherosclerosis or cholesterol levels and moderated the effects of IDE deficiency of bone marrow-derived cells. No differences were seen between Ldlr(-/-) and Ide(-/-)Ldlr(-/-) female mice reconstituted with Ide(-/-) or wild-type bone marrow. IDE deficiency in macrophages did not alter SR-A levels, cell surface SR-A, or foam cell formation.
  
  
  CONCLUSIONS
  IDE deficiency in bone marrow-derived cells results in larger atherosclerotic lesions, increased lesion-associated Aβ and RAGE, and higher serum cholesterol in male, Ldlr(-/-) mice.
authors.affiliation: University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Caravaggio
authors.forename: Mirela
authors.initials: M
authors.lastname: Hasu
authors.forename: Robin
authors.initials: R
authors.lastname: MacLaren
authors.forename: Mohamed
authors.initials: M
authors.lastname: Thabet
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Raizman
authors.forename: John P
authors.initials: JP
authors.lastname: Veinot
authors.forename: Yves L
authors.initials: YL
authors.lastname: Marcel
authors.forename: Ross W
authors.initials: RW
authors.lastname: Milne
authors.forename: Stewart C
authors.initials: SC
authors.lastname: Whitman
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000201:enzymology; D007339:Insulysin / Q000172:deficiency* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D008077:Lipoproteins, LDL; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051117:Scavenger Receptors, Class A; C032629:acetyl-LDL; D002784:Cholesterol; D007339:Insulysin
keywords: Amyloid; Atherosclerosis; Bone marrow transplantation; Insulin-degrading enzyme; LDL receptor-deficient mice; Receptor for advanced glycation end products (RAGE)