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.
Author:Flávia Figueiredo de Rezende FelipeORCiDGND, Franziska Moll, Maria Walter, Valeska HelfingerORCiDGND, Fabian Hahner, Patrick Janetzko, Christian Ringel, Andreas WeigertORCiDGND, Ingrid FlemingORCiD, Norbert Weißmann, Carsten Tobias Künne, Mario LoosoORCiDGND, Michael A. RiegerORCiDGND, Peter Nawroth, Thomas Fleming, Ralf Peter Louis BrandesORCiDGND, Katrin SchröderORCiDGND
Pubmed Id:
Parent Title (English):Redox Biology
Place of publication:Amsterdam [u. a.]
Document Type:Article
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
Page Number:10
First Page:12
Last Page:21
Under a Creative Commons license
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0