title: NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice.
abstract: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model.
  
  
  
  Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4(-/-)/Ldlr(-/-) mice. Further progression of endothelial dysfunction due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4(-/-)/Ldlr(-/-) mice compared with Ldlr(-/-) mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H2O2 production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4(-/-) mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo.
  
  
  
  Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H2O2 could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.
authors.affiliation: Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Langbein
authors.affiliation: Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Coy
authors.initials: C
authors.lastname: Brunssen
authors.affiliation: Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Clinical Sensoring and Monitoring, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Cimalla
authors.affiliation: Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Brux
authors.affiliation: Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Institute of Physiology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Clinical Sensoring and Monitoring, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: Edmund
authors.initials: E
authors.lastname: Koch
authors.affiliation: Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany henning.morawietz@tu-dresden.de.
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
mesh_terms: D000818:Animals; D050197:Atherosclerosis; D042783:Endothelial Cells; D006861:Hydrogen Peroxide; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D011973:Receptors, LDL
chemical_list: D011973:Receptors, LDL; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: Atherosclerosis; Endothelial dysfunction; Flow-mediated dilation; Ldlr−/− mice; NADPH oxidase 4; Nox4