title: Deletion of the angiotensin II type 1a receptor prevents atherosclerotic plaque rupture in apolipoprotein E-/- mice.
abstract: OBJECTIVE
  Angiotensin II is involved in the genesis of atherosclerosis. As the role of the angiotensin II type 1a (AT(1a)) receptor in plaque rupture is poorly understood, we assessed the hypothesis that the AT(1a)receptor contributes to atherosclerotic plaque rupture.
  
  
  RESULTS
  Atherosclerotic plaque rupture was induced by carotid artery ligation for 4 weeks followed by polyethylene cuff placement around the carotid in apolipoprotein E (ApoE)(-/-) and ApoE(-/-) AT(1a)(-/-) mice. The incidence of plaque rupture at 4 days after cuff placement was 72% in ApoE(-/-) mice compared with 24% in ApoE(-/-) AT(1a)(-/-) mice (P<0.01). Lipid accumulation, macrophage infiltration, expression of inflammatory cytokines, nicotinamide adenine dinucleotide phosphate-oxidase activity, and matrix metalloproteinase-9 activity in atherosclerotic plaque were markedly attenuated in ApoE(-/-) AT(1a)(-/-) compared with ApoE(-/-) mice. Oxidized low-density lipoprotein inhibited macrophage migration in ApoE(-/-) macrophages. In contrast, oxidized low-density lipoprotein-induced macrophage trapping was abolished in ApoE(-/-) AT(1a)(-/-) macrophages, and this was associated with decreased CD36 expression and focal adhesion kinase activity.
  
  
  CONCLUSIONS
  Conclusion- These results suggest that blocking the AT(1) receptor may reduce atherosclerotic plaque rupture and that AT(1a) receptor-mediated macrophage trapping, inflammation, oxidative stress, and matrix metalloproteinase activation may play crucial roles in plaque vulnerability.
authors.affiliation: Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 7910295, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Aono
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nagai
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nishimura
authors.forename: Katsuji
authors.initials: K
authors.lastname: Inoue
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ogimoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Okayama
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D017353:Gene Deletion; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D012422:Rupture, Spontaneous; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: C544066:Agtr1a protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008055:Lipids; D008077:Lipoproteins, LDL; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C099252:oxidized low density lipoprotein; D013481:Superoxides; D000804:Angiotensin II; D000068756:Valsartan; D019255:NADPH Oxidases; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D014633:Valine