Christoph Schürmann1, Flavia Rezende1, Christoph Kruse1, Yakub Yasar1, Oliver Löwe1, Christian Fork1, Bart van de Sluis2, Rolf Bremer3, Norbert Weissmann4, Ajay M Shah5, Hanjoong Jo6, Ralf P Brandes7, Katrin Schröder7. 1. 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. 2. Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. 3. HBB Datenkommunikation & Abrechnungssysteme, Hannover, Germany. 4. Member of the German Center for Lung Research (DZL), Excellencecluster Cardiopulmonary System, Justus-Liebig-University Giessen, Giessen, Germany. 5. Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK. 6. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. 7. 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.
Abstract
AIMS: 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. METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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