Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions
Open accessAbstract
Vascular reactive oxygen species (ROS) are known to be involved in atherosclerosis development and progression. NADPH oxidase 4 (Nox4) is a constitutively active ROS-producing enzyme that is highly expressed in the vascular endothelium. Nox4 is unique in its biology and has been implicated in vascular repair, however, the role of Nox4 in atherosclerosis is unknown. Therefore, to determine the effect of endothelial Nox4 on development of atherosclerosis, Apoe E-/- mice +/- endothelial Nox4 (ApoE-/- + EC Nox4) were fed a high cholesterol/high fat (Western) diet for 24 weeks. Significantly fewer atherosclerotic lesions were observed in the ApoE-/- + EC Nox4 mice as compared to the ApoE-/- littermates, which was most striking in the abdominal region of the aorta. In addition, markers of T cell populations were markedly different between the groups; T regulatory cell marker (FoxP3) was increased whereas T effector cell marker (T-bet) was decreased in aorta from ApoE-/- + EC Nox4 mice compared to ApoE-/- alone. We also observed decreased monokine induced by gamma interferon (MIG; CXCL9), a cytokine known to recruit and activate T cells, in plasma and tissue from ApoE-/- + EC Nox4 mice. To further investigate the link between endothelial Nox4 and MIG expression, we utilized cultured endothelial cells from our EC Nox4 transgenic mice and human cells with adenoviral overexpression of Nox4. In these cultured cells, upregulation of Nox4 attenuated endothelial cell MIG expression in response to interferon-gamma. Together these data suggest that endothelial Nox4 expression reduces MIG production and promotes a T cell distribution that favors repair over inflammation, leading to protection from atherosclerosis.
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In general, NOX4 shows protective effects in ApoE−/− mice.
“In general, NOX4 shows protective effects in ApoE−/− mice (194, 229, 230, 379, 552, 838).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [194]
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References 28 · Cited by 85
Research works printed but not linked: 1
- [16]Guzik B Sagan A Ludew D Mrowiecki W Chwala M Bujak-Gizycka B Filip G Grudzien G Kapelak B Zmudka K Mrowiecki T Sadowski J Korbut R Guzik TJ International Journal of Cardiology Int. J. Cardiol. Elsevier B.V 2013 168 2389 2396 PMC3819986 23506637
- Authors
- Craige, S. M., Kant, S., Reif, M., Chen, K., Pei, Y., Angoff, R., Sugamura, K., Fitzgibbons, T., & Keaney, J. F.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Kumamoto University Hospital (JP)
- Corresponding author
- Craige, Siobhan M.
- ORCID
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 89
- Pages
- 1-7
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC4783146
- OpenAlex
- W807567746
- Cited by
- 85
- References
- 28
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 6 · 2018: 8 · 2017: 15 · 2016: 9 · 2015: 3
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- NOX4, atherosclerosis, reactive oxygen species, ApoE-deficient mice, Western diet, Foxp3+ regulatory T cells, CXCL9, interferon-gamma, vascular inflammation, vascular repair, endothelial cells
- MeSH terms
- NADPH Oxidase 4, Animals, Aorta, Apolipoproteins E, Cells, Cultured, Endothelium, Vascular, Female, Humans, Immunoenzyme Techniques, Interferon-gamma, Male, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Blotting, Western, Cytokines, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Reverse Transcriptase Polymerase Chain Reaction, Cell Proliferation, Atherosclerosis, T-Lymphocytes, Regulatory, Mice, Real-Time Polymerase Chain Reaction
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