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Cited by 386Nitric Oxide and Endothelin EffectsNeutrophil, Myeloperoxidase and Oxidative MechanismsAtherosclerosis and Cardiovascular Diseases

NADPH Oxidase 1 Plays a Key Role in Diabetes Mellitus–Accelerated Atherosclerosis

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Gray, Stephen P., Di Marco, Elyse, Okabe, Jun, Szyndralewiez, Cedric, Heitz, Freddy, Montezano, Augusto C., de Haan, Judy B., Koulis, Christine +8 more·2013·Circulation
DOI 10.1161/circulationaha.112.132159
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Abstract

Background—: In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis. Methods and Results—: Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E–deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E–deficient mice with GKT137831 attenuated atherosclerosis development. Conclusions—: These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis.

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  • Studies have shown links between high NOX1 levels and hypertension, diabetes, ischemia/reperfusion injury, and coronary artery disease.

    “Increased NOX1 activity is associated with vascular disease, and studies have shown links between high NOX1 levels and hypertension (1015), diabetes (163, 380, 1003), ischemia/reperfusion injury (479), and coronary artery disease (393).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [380]

  • The role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models.

    “Altogether, the role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models (345, 380, 630, 854).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [380]

  • NOX4 deletion in the ApoE−/− mouse does not ameliorate diabetes-associated vasculopathy.

    “However, NOX4 deletion in the ApoE−/− mouse does not ameliorate diabetes-associated vasculopathy (380).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [380]

  • The effect of NOX1 in atherosclerosis is contradictory, with examples of improved outcomes for NOX1 deficient mice subjected to high fat diet and diabetic mouse models, whereas in other cases NOX1 deletion did not seem to have an effect.

    “The results of different studies are contradictory, with examples of improved outcomes for NOX1 deficient mice subjected to high fat diet (854) and diabetic mouse models (380), whereas in other cases, NOX1 deletion did not seem to have an effect (875).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [380]

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Research works printed but not linked: 1

  1. Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H. Novel human homologues of p47phox and p67phox par- ticipate in activation of superoxide-producing NADPH oxidases. J Biol Chem. 2003;278:25234-25246.

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Authors
Gray, S. P., Di Marco, E., Okabe, J., Szyndralewiez, C., Heitz, F., Montezano, A. C., de Haan, J. B., Koulis, C., El-Osta, A., Andrews, K. L., Chin-Dusting, J. P. F., Touyz, R. M., Wingler, K., Cooper, M. E., Schmidt, H. H. H. W., & Jandeleit-Dahm, K. A.
Affiliations
  • Baker Heart and Diabetes Institute (AU)
  • From the Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, Melbourne, Australia (S.P.G., E.D.M., J.B.d.H., C.K., M.E.C., K.A.J.-D.); the Department of Medicine, Monash University, Monash, Australia (E.D.M., M.E.C., K.A.J.-D.); Epigenetics in Human Health and Disease, Baker IDI Heart & Diabetes Institute, Melbourne, Australia (J.O., A.E.-O.); GenKyoTex SA, Geneva, Switzerland (C.S., F.H.); Ottawa Hospital Research Institute, Ottawa, Canada (A.C.M., R.M.T.); Institute of...
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2013-05-07
Volume
127
Issue
18
Pages
1888-1902
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.112.132159
OpenAlex
W2137012624
Cited by
386
References
56
Citations by year
2026: 12 · 2025: 22 · 2024: 24 · 2023: 17 · 2022: 20 · 2021: 29 · 2020: 41 · 2019: 28 · 2018: 24 · 2017: 33 · 2016: 37 · 2015: 43 · 2014: 39 · 2013: 16
FWCI
31.26
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • Diabetes Australia Research Trust
  • Ottawa Hospital Research Institute
  • Diabetes Australia
  • National Heart Foundation of Australia
  • Université de Genève
  • Canadian Institutes of Health Research
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
NOX1, diabetic atherosclerosis, hyperglycemia, oxidative stress, reactive oxygen species, GKT137831, aortic endothelial cells, ApoE-deficient mice, atherosclerotic plaque, chemokine expression, leukocyte adhesion, macrophage infiltration, vascular inflammation
MeSH terms
NADPH Oxidase 1, Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Humans, Male, Mice, Transgenic, NADH, NADPH Oxidoreductases, Organ Culture Techniques, Reactive Oxygen Species, Mice, Knockout, Inflammation Mediators, NADPH Oxidases, Protein Isoforms, Endothelial Cells, Atherosclerosis, Mice

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