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The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice

  • Aim: NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes. Results: In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice. Innovation and conclusion: ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
Metadaten
Author:Flávia Figueiredo de Rezende FelipeORCiDGND, Franziska Moll, Maria Walter, Valeska HelfingerORCiDGND, Fabian HahnerORCiD, Patrick JanetzkoGND, Christian Ringel, Andreas WeigertORCiDGND, Ingrid FlemingORCiD, Norbert WeißmannGND, Carsten Tobias KünneORCiDGND, Mario LoosoORCiDGND, Michael A. RiegerORCiDGND, Peter Nawroth, Thomas Fleming, Ralf BrandesORCiDGND, Katrin SchröderORCiDGND
URN:urn:nbn:de:hebis:30:3-463829
DOI:https://doi.org/10.1016/j.redox.2017.11.014
ISSN:2213-2317
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29195137
Parent Title (English):Redox Biology
Publisher:Elsevier
Place of publication:Amsterdam [u. a.]
Document Type:Article
Language:English
Year of Completion:2017
Date of first Publication:2017/11/22
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/05/03
Tag:NADPH oxidase; Nox1; NoxO1; Reactive oxygen species; Superoxide; p47phox
Volume:15
Page Number:10
First Page:12
Last Page:21
Note:
Under a Creative Commons license
HeBIS-PPN:432042466
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0