title: Deficiency of receptor-associated protein attenuates angiotensin II-induced atherosclerosis in hypercholesterolemic mice without influencing abdominal aortic aneurysms.
abstract: OBJECTIVE
  Receptor-associated protein (RAP) was initially described as a regulator of low density lipoprotein receptor-related protein 1 (LRP1), but is now known to regulate many proteins. Since the direct effects of RAP on vascular pathologies have not been studied, this study determined whether RAP deficiency influenced angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice.
  
  
  RESULTS
  Male LDL receptor -/- mice that were either RAP +/+ or -/- were infused with AngII (500 ng/kg/min) for 4 weeks while consuming a saturated fat-enriched diet. RAP deficiency had no effects on body weight or AngII-induced increases of systolic blood pressure. Despite increased plasma cholesterol concentrations, RAP deficiency reduced atherosclerotic lesion size in aortic arches, while having no effect on AngII-induced AAAs. RAP deficiency profoundly reduced LRP1 protein abundance in macrophages, but did not change its abundance in aortic smooth muscle cells. Also, RAP deficiency had no effects on mRNA abundance of LRP1 or lipoprotein lipase in macrophages. To determine whether RAP deficiency in leukocytes influenced AngII-induced atherosclerosis, irradiated male LDL receptor -/- mice were repopulated with bone marrow-derived cells from either RAP +/+ or -/- male mice. The chimeric mice were infused with AngII (500 ng/kg/min) for 4 weeks while fed the saturated fat-enriched diet. RAP deficiency in bone marrow-derived cells did not influence either plasma cholesterol concentrations or atherosclerotic lesion size.
  
  
  CONCLUSIONS
  Whole body RAP deficiency attenuated atherosclerosis without influencing AAAs in hypercholesterolemic mice infused with AngII. The anti-atherogenic effect was not attributable to RAP deficiency in bone marrow-derived cells.
authors.affiliation: 28th Division, Beijing An Zhen Hospital, Capital Medical University, Beijing 100029, China.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wang
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Subramanian
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Howatt
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Moorleghen
authors.forename: Richard
authors.initials: R
authors.lastname: Charnigo
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
mesh_terms: D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D026563:LDL-Receptor Related Protein-Associated Protein / Q000172:deficiency* / Q000235:genetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D002784:Cholesterol