title: Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice.
abstract: Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE(-/-) mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(-/-) mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis.
authors.affiliation: 1] Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan [2] Service of Rheumatology, Department of l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Johji
authors.initials: J
authors.lastname: Nomura
authors.affiliation: Service of Rheumatology, Department of l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
authors.affiliation: Service of Rheumatology, Department of l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Ives
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Matsui
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Tsujimoto
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirakura
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Tsunefumi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Service of Rheumatology, Department of l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D000069465:Febuxostat; D006074:Gout Suppressants / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D006074:Gout Suppressants; D017382:Reactive Oxygen Species; D013844:Thiazoles; D000069465:Febuxostat; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D014969:Xanthine Oxidase