Deletion of NoxO1 limits atherosclerosis development in female mice

• Type of Material: Article
• Authors: Giulia K. Buchmann, Goethe University; Christoph Schuermann, Goethe University; Tim Warwick, Goethe University; Marcel H. Schulz, German Center for Cardiovascular Research; Manuela Spaeth, Goethe University; Oliver J. Mueller, University of Kiel; Katrin Schroeder, Goethe University; Hanjoong Jo, Emory University; Norbert Weissmann, University of Giessen; Ralf P. Brandes, Goethe University
• Language: English
• Date: 2020-10-01
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.redox.2020.101713
• Title of Journal or Parent Work: REDOX BIOLOGY
• Volume: 37
• Start Page: 101713
• End Page: 101713
• Grant/Funding Information: This work was supported by grants from the Deutsche Forschungsgemeinschaft (Auflösung von Entzündungen; GRK 2336, Sonderforschungsbereich 834 - Teilproject A2, excellence cluster EXS2026 Cardio-Pulmonary Institute) and by German Center for Cardiovascular Research (81X220014/81X2700221, and professorship of MS). HJ was supported by funding from the National Institutes of Health grants HL119798 and HL095070.
• Keywords: Life Sciences & Biomedicine; NoxO1; Biochemistry & Molecular Biology; Reactive oxygen species; Gender differences; GENERATION; SUPEROXIDE-PRODUCTION; Science & Technology; PCSK9; NADPH oxidase; NADPH OXIDASES; PROGRESSION; GENDER-DIFFERENCES; Atherosclerosis; ATHEROPROTECTION; OXIDASE SUBUNIT NOXO1; EXPRESSION; TARGET; INFLAMMATION
• Research Categories: Health Sciences, Medicine and Surgery; Gender Studies

Abstract

Objective: Oxidative stress is a risk factor for atherosclerosis. NADPH oxidases of the Nox family produce ROS but their contribution to atherosclerosis development is less clear. Nox2 promotes and Nox4 rather limits atherosclerosis. Although Nox1 with its cytosolic co-factors are largely expressed in epithelial cells, a role for Nox1 for atherosclerosis development was suggested. To further define the role of this homologue, the role of its essential cytosolic cofactor, NoxO1, was determined for atherosclerosis development with the aid of knockout mice. Methods and results: Wildtype (WT) and NoxO1 knockout mice were treated with high fat diet and adeno-associated virus (AAV) overexpressing pro-protein convertase subtilisin/kexin type 9 (PCSK9) to induce hepatic low-density lipoprotein (LDL) receptor loss. As a result, massive hypercholesterolemia was induced and spontaneous atherosclerosis developed within three month. Deletion of NoxO1 reduced atherosclerosis formation in brachiocephalic artery and aortic arch in female but not male NoxO1−/− mice as compared to WT littermates. This was associated with a reduced pro-inflammatory cytokine signature in the plasma of female but not male NoxO1−/− mice. MACE-RNAseq of the vessel did not reveal this signature and the expression of the Nox1/NoxO1 system was low to not detectable. Conclusions: The scaffolding protein NoxO1 plays some role in atherosclerosis development in female mice probably by attenuating the global inflammatory burden.