title: Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development.
abstract: OBJECTIVE
  Hyperuricemia is common in patients with metabolic syndrome. We investigated the role of xanthine oxidoreductase (XOR) in atherosclerosis development, and the effects of the XOR inhibitor allopurinol on this process.
  
  
  RESULTS
  Oral administration of allopurinol to ApoE knockout mice markedly ameliorated lipid accumulation and calcification in the aorta and aortic root. In addition, allopurinol treatment or siRNA-mediated gene knockdown of XOR suppressed transformation of J774.1 murine macrophage cells, treated with acetylated LDL or very low density lipoprotein (VLDL) into foam cells. This inhibitory effect of allopurinol was also observed in primary cultured human macrophages. In contrast, overexpression of XOR promoted transformation of J774.1 cells into foam cells. Interestingly, SR-A1, SR-B1, SR-B II, and VLDL receptors in J774.1 cells were reduced by XOR knockdown, and increased by XOR overexpression. Conversely, expressions of ABCA1 and ABCG1 were increased by XOR knockdown and suppressed by XOR overexpression. Finally, productions of inflammatory cytokines accompanied by foam cell formation were also reduced by allopurinol administration.
  
  
  CONCLUSIONS
  These results strongly suggest XOR activity and/or its expression level to contribute to macrophage foam cell formation. Thus, XOR inhibitors may be useful for preventing atherosclerosis.
authors.affiliation: 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Okubo
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Takako
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sato
authors.forename: Sakura
authors.initials: S
authors.lastname: Kushiyama
authors.forename: Misaki
authors.initials: M
authors.lastname: Iwashita
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawazu
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Higashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*
chemical_list: C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D016207:Cytokines; D004791:Enzyme Inhibitors; D008074:Lipoproteins; D000493:Allopurinol; D014968:Xanthine Dehydrogenase