Maqbool, A. orcid.org/0000-0003-4911-9881, Viswambharan, H., Skromna, A. et al. (11 more authors) (2024) Whole-body insulin resistance leads to accelerated atherosclerosis: role for Nox2 NADPH oxidase. Vascular Biology, 6 (1). e230018. ISSN 2516-5658
Abstract
Insulin resistance underpins the progression of type 2 diabetes mellitus and leads to a collection of risk factors for the development of atherosclerosis. Whether or not insulin resistance at a whole-body level per se leads to accelerated atherosclerosis is unclear. To answer this question, we generated atherosclerosis-prone mice with whole-body insulin resistance secondary to haploinsufficiency of the insulin receptor (IR+/−) deficient in ApoE−/− (IR+/−/ApoE−/−). IR+/−/ ApoE−/− and ApoE−/− littermates had similar weight, lipids, and glucose tolerance at baseline. After 12 weeks of Western high-cholesterol diet, IR+/−/ApoE−/− had significantly more atherosclerosis in the thoracoabdominal aorta and at the level of the aortic sinus than ApoE−/− littermates. Excess Nox2 NADPH oxidase (Nox2) derived superoxide has been suggested to underpin diabetes-related atherosclerosis. In IR+/−/ApoE−/− we examined the effect of inhibiting Nox2 using genetic or pharmacological approaches on the development of atherosclerosis. To genetically delete Nox2, we generated IR+/−/ApoE−/−/Nox2−/y and to inhibit Nox2 pharmacologically, we treated IR+/−/ApoE−/− with the peptide Nox2 inhibitor gp91dstat. IR+/−/ApoE−/−/Nox2−/y had significant disruption of the aortic wall with increased thoracoabdominal atherosclerosis when compared to IR+/−/ApoE−/−/Nox2+/y littermates. Inhibition of Nox2 using gp91dstat reduced atherosclerosis in the thoracoabdominal aorta of IR+/−/ApoE−/−. Whole-body insulin resistance accelerates the development of atherosclerosis. Genetic inhibition of Nox2 leads to disruption of the aortic wall in IR+/−/ApoE−/− mice with accelerated atherosclerosis, whereas pharmacological Nox2 inhibition reduces atherosclerosis in IR+/−/ApoE−/− without disruption of the arterial wall.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | atherosclerosis; insulin resistance; Nox2 NADPH oxidase |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 29 Nov 2024 10:32 |
Last Modified: | 29 Nov 2024 10:33 |
Published Version: | https://vb.bioscientifica.com/view/journals/vb/6/1... |
Status: | Published |
Publisher: | BioScientifica |
Identification Number: | 10.1530/vb-23-0018 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:220241 |