title: NADPH oxidase deficiency exacerbates angiotensin II-induced abdominal aortic aneurysms in mice.
abstract: OBJECTIVE
  Although nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) is reportedly essential for phagocyte host defenses, it has been found to aggravate atherosclerosis in apolipoprotein E (Apoe)-null mice through excess production of superoxide. We therefore assessed the role of NOX2 in an experimental model of abdominal aortic aneurysm (AAA) and assessed the mechanism of NOX2 action in AAA.
  
  
  RESULTS
  AAA was induced in low-density lipoprotein receptor-null (Ldlr(-/-)) mice by infusing angiotensin II. Nox2 expression was elevated in the abdominal aortae of these mice during infusion of angiotensin II, with enhanced Nox2 expression mainly because of the recruitment of NOX2-enriched macrophages into AAA lesions. Unexpectedly, systemic Nox2 deficiency promoted AAA development but reduced the level of reactive oxygen species in AAA lesions. Nox2 deficiency stimulated macrophage conversion toward the M1 subset, enhancing expression of interleukin (IL)-1β and matrix metalloproteinase-9/12 mRNA. Administration of neutralizing antibody against IL-1β abolished AAA development in Nox2-deficient mice. Bone marrow transplantation experiments revealed that AAA aggravation by Nox2 deficiency is because of bone marrow-derived cells. Isolated bone marrow-derived macrophages from Nox2-null mice could not generate reactive oxygen species. In contrast, IL-1β expression in peritoneal and bone marrow-derived macrophages, but not in peritoneal neutrophils, was substantially enhanced by Nox2 deficiency. Pharmacological inhibition of Janus kinase/signal transducers and activators of transcription signaling inhibited excess IL-1β expression in Nox2-deficient macrophages, whereas matrix metalloproteinase-9 secretion was constitutively stimulated via nuclear factor-κB signals.
  
  
  CONCLUSIONS
  Nox2 deficiency enhances macrophage secretion of IL-1β and matrix metalloproteinase-9, disrupting tissue-remodeling functions in AAA lesions. These actions are unfavorable if NOX2 is to serve as a molecular target for AAA.
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Kigawa
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.). taku@pharm.showa-u.ac.jp.
authors.forename: Takuro
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Lei
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamachi
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Oguchi
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Joo-ri
authors.initials: JR
authors.lastname: Kim-Kaneyama
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Matsuo
authors.initials: M
authors.lastname: Taniyama
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Shohko
authors.initials: S
authors.lastname: Tsunawaki
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.affiliation: From the Department of Biochemistry (Y.K., T.M., X.-F.L., T.O., J.-r.K.-K., S.T., A.M.) and Department of Anatomy (T.N., S.S.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.N.); Division of Endocrinology and Metabolism, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan (Y.K., M.T.); and Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan (T.N.).
authors.forename: Akira
authors.initials: A
authors.lastname: Miyazaki
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000906:Antibodies; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053508:Matrix Metalloproteinase 12
keywords: NADPH oxidase; aortic aneurysm, abdominal; cytokines; macrophages; oxidative stress