title: The NADPH oxidase Nox4 has anti-atherosclerotic functions.
abstract: OBJECTIVE
  Oxidative stress is thought to be a risk for cardiovascular disease and NADPH oxidases of the Nox family are important producers of reactive oxygen species. Within the Nox family, the NADPH oxidase Nox4 has a unique position as it is constitutively active and produces H2O2 rather than [Formula: see text] . Nox4 is therefore incapable of scavenging NO and its low constitutive H2O2 production might even be beneficial. We hypothesized that Nox4 acts as an endogenous anti-atherosclerotic enzyme.
  
  
  RESULTS
  Tamoxifen-induced Nox4-knockout mice were crossed with ApoE⁻/⁻ mice and spontaneous atherosclerosis under regular chow as well as accelerated atherosclerosis in response to partial carotid artery ligation under high-fat diet were determined. Deletion of Nox4 resulted in increased atherosclerosis formation in both models. Mechanistically, pro-atherosclerotic and pro-inflammatory changes in gene expression were observed prior to plaque development. Moreover, inhibition of Nox4 or deletion of the enzyme in the endothelium but not in macrophages resulted in increased adhesion of macrophages to the endothelial surface.
  
  
  CONCLUSIONS
  The H2O2-producing NADPH oxidase Nox4 is an endogenous anti-atherosclerotic enzyme. Nox4 inhibitors, currently under clinical evaluation, should be carefully monitored for cardiovascular side-effects.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schürmann
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
authors.forename: Flavia
authors.initials: F
authors.lastname: Rezende
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kruse
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
authors.forename: Yakub
authors.initials: Y
authors.lastname: Yasar
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Löwe
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Fork
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: HBB Datenkommunikation & Abrechnungssysteme, Hannover, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bremer
authors.affiliation: Member of the German Center for Lung Research (DZL), Excellencecluster Cardiopulmonary System, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany brandes@vrc.uni-frankfurt.de schroeder@vrc.uni-frankfurt.de.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany brandes@vrc.uni-frankfurt.de schroeder@vrc.uni-frankfurt.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000503:physiopathology*; D002339:Carotid Arteries / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: ApoE; Arteriosclerosis; Inflammation; Lipids; NADPH oxidase; Reactive oxygen species; Remodelling