Maqbool, A, Watt, N, Haywood, N et al. (17 more authors) (2020) Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance related vascular damage. American Journal of Physiology: Cell Physiology. ISSN 0363-6143
Abstract
Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on: superoxide generation in saphenous vein EC (SVEC) from patients with advanced atherosclerosis and type 2 diabetes; and on vascular function, vascular damage and lipid deposition in Apolipoprotein E deficient (ApoE-/-) mice with EC specific insulin resistance (ESMIRO). To examine the effect of genetic inhibition of Nox2, ESMIRO mice deficient in ApoE-/- and Nox2 (ESMIRO/ApoE-/-/Nox2-/y) were generated and compared to ESMIRO/ApoE-/-/Nox2+/y littermates. To examine the effect of pharmacological inhibition of Nox2 we administered gp91dstat or scrambled peptide to ESMIRO/ApoE-/- mice. SVEC from diabetic patients had increased expression of Nox2 protein with concomitant increase in superoxide generation which could be reduced by the Nox2 inhibitor gp91dstat. After 12 weeks western diet, ESMIRO/ApoE-/-/Nox2-/y mice had reduced EC superoxide generation and greater aortic relaxation to acetylcholine. ESMIRO/ApoE-/-/Nox2-/y mice developed more lipid deposition in the thoraco-abdominal aorta with multiple foci of elastin fragmentation at the level of the aortic sinus and greater expression of intercellular adhesion molecule-1 (ICAM-1). Gp91dstat reduced EC superoxide and lipid deposition in the thoraco-abdominal aorta of ESMIRO/ApoE-/- mice without causing elastin fragmentation or increased ICAM-1 expression. These results demonstrate that insulin resistance is characterized by increased Nox2-derived vascular superoxide. Complete deletion of Nox2 in mice with EC insulin resistance exacerbates, whereas partial pharmacological Nox2 inhibition protects against, insulin resistance-induced vascular damage.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020, American Journal of Physiology-Cell Physiology. This is an author produced version of a paper published in the American Journal of Physiology - Cell Physiology. Uploaded in accordance with the publisher's self-archiving policy. |
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) |
Funding Information: | Funder Grant number British Heart Foundation PG/14/54/30939 |
Depositing User: | Symplectic Publications |
Date Deposited: | 14 May 2020 15:04 |
Last Modified: | 13 May 2021 00:38 |
Status: | Published online |
Publisher: | American Physiological Society |
Identification Number: | 10.1152/ajpcell.00389.2019 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:160688 |