title: Bone marrow angiotensin AT2 receptor deficiency aggravates atherosclerosis development by eliminating macrophage liver X receptor-mediated anti-atherogenic actions.
abstract: BACKGROUND
  Bone marrow (BM) Angiotensin II (Ang II) type 1 (AT1) receptor plays a crucial role in atherosclerosis development; however, the effect of BM Ang II type 2 (AT2) receptor on atherogenesis remains undefined.
  
  
  RESULTS
  We generated BM chimera apoE-deficient (apoE(-/-)) mice whose BM cells were repopulated with AT2-deficient (Agtr2(-/-)) or wild-type (Agtr2(+/+)) cells. After 2 months of a high-cholesterol diet, the atherosclerotic lesion area was significantly increased in the apoE(-/-)/BM-Agtr2(-/-) mice compared with the apoE(-/-)/BM-Agtr2(+/+) mice (51%, P < 0.05), accompanied by an augmented accumulation of lesion macrophages. Although phenotypic polarization in BM-derived macrophages and lipopolysaccharide-induced expression of proinflammatory cytokines in thioglycollate-induced peritoneal macrophages (TGPMs) were not affected by AT2-deficiency, mRNA and protein expression levels of macrophage liver X receptor β (LXRβ) were significantly decreased in Agtr2(-/-) TGPMs compared with Agtr2(+/+) TGPMs. Anti-inflammatory effects of LXR agonist (GW3965) were markedly inhibited in Agtr2(-/-) TGPMs. Furthermore, the expression levels of ATP-binding cassette transporter ABCA1 and CCR7 were much lower in Agtr2(-/-) TGPMs than Agtr2(+/+) TGPMs, accompanied by a significantly reduced cholesterol efflux.
  
  
  CONCLUSIONS
  Our findings demonstrate that BM-AT2 deficiency aggravates atherosclerosis, at least in part, by eliminating the anti-atherogenic properties of macrophages elicited by LXRβ activation.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawahito
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Sou
authors.initials: S
authors.lastname: Kishida
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Irie
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Wakana
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kikai
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takata
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan hiyamada@koto.kpu-m.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001692:Biological Transport; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D016764:Cell Polarity; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010641:Phenotype; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency* / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D013864:Thioglycolates
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002784:Cholesterol; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D044139:Receptor, Angiotensin, Type 2; D054400:Receptors, CCR7; D013864:Thioglycolates; C577833:Abca1 protein, mouse; C515371:Ccr7 protein, mouse; C017487:2-mercaptoacetate
keywords: Angiotensin; atherosclerosis; liver X receptor; macrophage; receptor