Redox Modulation of Endothelial Nitric Oxide Synthase by Glutaredoxin-1 through Reversible Oxidative Post-Translational Modification
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S-Glutathionylation is a redox-regulated modification that uncouples endothelial nitric oxide synthase (eNOS), switching its function from nitric oxide (NO) synthesis to (•)O2(-) generation, and serves to regulate vascular function. While in vitro or in vivo eNOS S-glutathionylation with modification of Cys689 and Cys908 of its reductase domain is triggered by high levels of glutathione disulfide (GSSG) or oxidative thiyl radical formation, it remains unclear how this process may be reversed. Glutaredoxin-1 (Grx1), a cytosolic and glutathione-dependent enzyme, can reverse protein S-glutathionylation; however, its role in regulating eNOS S-glutathionylation remains unknown. We demonstrate that Grx1 in the presence of glutathione (GSH) (1 mM) reverses GSSG-mediated eNOS S-glutathionylation with restoration of NO synthase activity. Because Grx1 also catalyzes protein S-glutathionylation with an increased [GSSG]/[GSH] ratio, we measured its effect on eNOS S-glutathionylation when the [GSSG]/[GSH] ratio was >0.2, which can occur in cells and tissues under oxidative stress, and observed an increased level of eNOS S-glutathionylation with a marked decrease in eNOS activity without uncoupling. This eNOS S-glutathionylation was reversed with a decrease in the [GSSG]/[GSH] ratio to <0.1. Liquid chromatography and tandem mass spectrometry identified a new site of eNOS S-glutathionylation by Grx1 at Cys382, on the surface of the oxygenase domain, without modification of Cys689 or Cys908, each of which is buried within the reductase. Furthermore, Grx1 was demonstrated to be a protein partner of eNOS in vitro and in normal endothelial cells, supporting its role in eNOS redox regulation. In endothelial cells, Grx1 inhibition or gene silencing increased the level of eNOS S-glutathionylation and decreased the level of cellular NO generation. Thus, Grx1 can exert an important role in the redox regulation of eNOS in cells.
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At least three eNOS residues are susceptible to S-glutathionylation: Cys689, Cys908, and Cys382.
“At least three residues have been shown to be susceptible: Cys689, Cys908 (162), and Cys382 (160)”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [160]
S-glutathionylation of eNOS can be reversed by glutaredoxin-1.
“The process can be reversed by glutaredoxin-1 (160).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [160]
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- Authors
- Chen, C.-A., De Pascali, F., Basye, A., Hemann, C., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- Department of Emergency Medicine and ‡Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States
- Corresponding author
- Chen, Chun-An
- Zweier, Jay L.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-09-11
- Volume
- 52
- Issue
- 38
- Pages
- 6712-6723
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC3813969
- OpenAlex
- W1980021377
- Cited by
- 71
- References
- 46
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 6 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 6
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL063744, R01-HL65608, R01HL63744, P01HL065608, R01HL38324, R01HL038324, R00HL103846, K99HL103846)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- endothelial nitric oxide synthase, glutaredoxin 1, S-glutathionylation, redox regulation, glutathione disulfide, glutathione, oxidative post-translational modifications, nitric oxide production, eNOS uncoupling, reductase domain, oxygenase domain, endothelial cells, oxidative stress
- MeSH terms
- Animals, Cadmium, Cattle, Cells, Cultured, Cysteine, Endothelium, Vascular, Glutathione, Humans, Oxidation-Reduction, Protein Processing, Post-Translational, Protein Structure, Tertiary, Glutathione Disulfide, Gene Silencing, Nitric Oxide Synthase Type III, Glutaredoxins
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