Cited by 299Nitric Oxide and Endothelin EffectsAtherosclerosis and Cardiovascular DiseasesNeutrophil, Myeloperoxidase and Oxidative Mechanisms

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Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/−mice

Judkins, Courtney P., Diep, Henry, Broughton, Brad R. S., Mast, Anja E., Hooker, Elizabeth U., Miller, Alyson A., Selemidis, Stavros, Dusting, Gregory J., Sobey, Christopher G., Drummond, Grant R.·2010·American Journal of Physiology-Heart and Circulatory Physiology

DOI 10.1152/ajpheart.00799.2009

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Abstract

The Nox family NADPH oxidases are reactive oxygen species (ROS)-generating enzymes that are strongly implicated in atherogenesis. However, no studies have examined which Nox isoform(s) are involved. Here we investigated the role of the Nox2-containing NADPH oxidase in atherogenesis in apolipoprotein E-null (ApoE−/−) mice. Wild-type (C57Bl6/J), ApoE−/−, and Nox2−/y/ApoE−/−mice were maintained on a high-fat (21%) diet from 5 wk of age until they were 12 or 19 wk old. Mice were euthanized and their aortas removed for measurement of Nox2 expression (Western blot analysis and immunohistochemistry), ROS production (L012-enhanced chemiluminescence), nitric oxide (NO) bioavailability (contractions to N ω-nitro-l-arginine), and atherosclerotic plaque development along the aorta and in the aortic sinus. Nox2 expression was upregulated in the aortic endothelium of ApoE−/−mice before the appearance of lesions, and this was associated with elevated ROS levels. Within developing plaques, macrophages were also a prominent source of Nox2. The absence of Nox2 in Nox2−/y/ApoE−/−double-knockout mice had minimal effects on plasma lipids or lesion development in the aortic sinus in animals up to 19 wk of age. However, an en face examination of the aorta from the arch to the iliac bifurcation revealed a 50% reduction in lesion area in Nox2−/y/ApoE−/−versus ApoE−/−mice, and this was associated with a marked decrease in aortic ROS production and an increased NO bioavailability. In conclusion, this is the first demonstration of a role for Nox2-NADPH oxidase in vascular ROS production, reduced NO bioavailability, and early lesion development in ApoE−/−mice, highlighting this Nox isoform as a potential target for future therapies for atherosclerosis.

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Background
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Authors: Judkins, C. P., Diep, H., Broughton, B. R. S., Mast, A. E., Hooker, E. U., Miller, A. A., Selemidis, S., Dusting, G. J., Sobey, C. G., & Drummond, G. R.
Affiliations: Monash University (AU)
The University of Melbourne (AU)
ORCID: Judkins, Courtney P.
Diep, Henry
Broughton, Brad R. S.
Miller, Alyson A.
Selemidis, Stavros
Dusting, Gregory J.
Sobey, Christopher G.
Drummond, Grant R.
Venue: American Journal of Physiology-Heart and Circulatory Physiology
Publisher: American Physiological Society
Published: 2010-01
Volume: 298
Issue: 1
Pages: H24-H32
ISSN: 0363-6135 (ISSN-L)
1522-1539
DOI: 10.1152/ajpheart.00799.2009
OpenAlex: W2157615046
Cited by: 299
References: 30
Citations by year: 2026: 10 · 2025: 11 · 2024: 12 · 2023: 15 · 2022: 10 · 2021: 16 · 2020: 12 · 2019: 11 · 2018: 15 · 2017: 20 · 2016: 23 · 2015: 30 · 2014: 34 · 2013: 23 · 2012: 25
FWCI: 12.37
Type: journal article
Language: en
Open access: closed
Locations: American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
PubMed (publishedVersion)
Research Bank (Australian Catholic University) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords: NOX2, NADPH oxidase, superoxide production, reactive oxygen species, nitric oxide bioavailability, atherosclerosis, atherosclerotic plaque formation, apolipoprotein E deficiency, macrophages, aortic endothelium, high-fat diet
MeSH terms: NADPH Oxidase 2, Animals, Aorta, Thoracic, Apolipoproteins E, Biological Availability, Enzyme Inhibitors, Hypercholesterolemia, Immunohistochemistry, Isoenzymes, Lipids, Male, Membrane Glycoproteins, Muscle Contraction, Muscle, Smooth, Vascular, Nitric Oxide, Superoxides, Blotting, Western, Reactive Oxygen Species, Mice, Knockout, NADPH Oxidases, NG-Nitroarginine Methyl Ester, Atherosclerosis, Mice

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Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/−mice

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