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NADPH Oxidase Deficiency Exacerbates Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice

Yasuyoshi KigawaFrom 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.)Takuro MiyazakiFrom 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.)Xiao‐Feng LeiFrom 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.)Tomoya NakamachiFrom 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.)Tatsunori OguchiFrom 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.)Joo‐ri Kim‐KaneyamaFrom 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.)Matsuo TaniyamaFrom 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.)Shohko TsunawakiFrom 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.)Seiji ShiodaFrom 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.)Akira MiyazakiFrom 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.)

2014en

ABI

Annotatsiya

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. APPROACH AND 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.

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DOI: 10.1161/atvbaha.114.303086

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