The p47phox- and NADPH oxidase organiser 1 (NOXO1)-dependent activation of NADPH oxidase 1 (NOX1) mediates endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction in a streptozotocin-induced murine model of diabetes
Open accessAbstract
Aims/hypothesis We have previously shown that NADPH oxidase (NOX) lies upstream of uncoupled endothelial nitric oxide synthase (eNOS), which is known to occur in diabetic endothelium. However, it remains unclear which specific NOX isoform(s) is responsible for eNOS uncoupling and endothelial dysfunction in diabetic mouse models. The aim of the present study was to test the hypothesis that one or more NOX isoform(s) mediate(s) diabetic uncoupling of eNOS, which has been shown to occur in patients with diabetes to contribute to endothelial dysfunction.Methods Diabetes was induced by streptozotocin administration. The N (ω)-nitro-L-arginine methyl ester (L-NAME)-sensitive superoxide production of aortic segments, reflective of eNOS uncoupling activity, was determined by electron spin resonance.Results The L-NAME-sensitive superoxide production was more than doubled in wild-type diabetic mice, implicating uncoupling of eNOS. This was abolished in diabetic p47 ( phox-/-) (also known as Ncf1 (-/-)) mice, but preserved in Nox2 (-/y) (also known as Cybb (-/-)) mice made diabetic. The eNOS uncoupling activity was markedly attenuated in diabetic mice transfected with Nox1 or Nox1 organiser 1 (Noxo1) short interfering RNA (siRNA), and abolished in Nox1 (-/y) diabetic mice. Diabetes-induced impairment in endothelium-dependent vasorelaxation was also significantly attenuated in the Nox1 (-/y) mice made diabetic. By contrast, Nox4 siRNA, or inhibition of mitochondrial complex I or III with rotenone or siRNA, respectively, had no effect on diabetic uncoupling of eNOS. Overexpression of Dhfr, or oral administration of folic acid to improve dihydrofolate reductase (DHFR) function, recoupled eNOS in diabetes to improve endothelial function.Conclusions/interpretation Our data demonstrate for the first time that the p47(phox) and NOXO1-dependent activation of NOX1, but not that of NOX2, NOX4 or mitochondrion, mediates diabetic uncoupling of eNOS. NOX1-null mice are protected from diabetic endothelial dysfunction. Novel approaches to inhibit NOX1 and/or improve DHFR function, may prove to have therapeutic potential for diabetic endothelial dysfunction.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mitochondrial ROS have been implicated in pathways leading to cell proliferation and senescence and in activation of JNK and NF-κB.
“Additionally, mitochondrial ROS have been implicated in pathways leading to cell proliferation and senescence (233, 1046) as well as in the activation of other major cell signaling molecules such as the MAP kinase JNK and NF-κB (330, 689).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1046]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 33 · Cited by 128
- Authors
- Youn, J. Y., Gao, L., & Cai, H.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Cai, H.
- Venue
- Diabetologia
- Published
- 2012-05-02
- Volume
- 55
- Issue
- 7
- Pages
- 2069-2079
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC3694990
- OpenAlex
- W2026685522
- Cited by
- 128
- References
- 33
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 12 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 5 · 2017: 10 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 11 · 2012: 8
- FWCI
- 9.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- National Heart, Lung, and Blood Institute (R01HL077440, HL 101228, HL077440, R01HL108701, HL-088975, R01HL088975, R01HL101228)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NOX1, NADPH oxidase 2, p47phox, NOXO1, eNOS uncoupling, endothelial dysfunction, diabetes mellitus, streptozotocin-induced diabetes, superoxide production, dihydrofolate reductase, folic acid, endothelium-dependent relaxation, mitochondrial complex I
- MeSH terms
- NADPH Oxidase 1, Animals, Diabetes Mellitus, Experimental, Endothelium, Vascular, Male, Mice, Inbred C57BL, NADH, NADPH Oxidoreductases, Proteins, Vasodilation, NADPH Oxidases, Adaptor Proteins, Signal Transducing, Mice, Nitric Oxide Synthase Type III
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
