ArticleJournal of the American Heart Association2014
Glutathionylation mediates angiotensin II-induced eNOS uncoupling, amplifying NADPH oxidase-dependent endothelial dysfunction.
Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 86 citations in OpenAlex.
- eNOS Uncoupling, Shear-Stress Tolerance, and the Two-Threshold Model of Post-Exertional Malaise in Long COVID: A Mechanistic Hypothesis With Implications for Physiotherapy and Recovery Protocols.Microcirculation (New York, N.Y. : 1994) · 2026Review
- The core mechanism of hypertension-linked renal fibrosis: "RAAS-ROS-inflammation-fibrosis" axis.iScience · 2026Review
- The Ever-Expanding Influence of the Endothelial Nitric Oxide Synthase.Basic & clinical pharmacology & toxicology · 2025Review
- Oxidative Stress and Erectile Dysfunction: Pathophysiology, Impacts, and Potential Treatments.Current issues in molecular biology · 2024Review
- 2-Amino-Molecules (Basel, Switzerland) · 2024Article
- Hypertension and Dyslipidemia: the Two Partners in Endothelium-Related Crime.Current atherosclerosis reports · 2023Review
- Celiac ganglia neurolysis suppresses high blood pressure in rats.Hypertension research : official journal of the Japanese Society of Hypertension · 2023Article
- Targeting cytokine-like protein FAM3D lowers blood pressure in hypertension.Cell reports. Medicine · 2023Article
- Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets.Cellular & molecular biology letters · 2023Article
- The Renin-Angiotensin-Aldosterone System, Nitric Oxide, and Hydrogen Sulfide at the Crossroads of Hypertension and COVID-19: Racial Disparities and Outcomes.International journal of molecular sciences · 2022Review
- Lipoxin alleviates oxidative stress: a state-of-the-art review.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Review
- Review
- The Endothelial Dysfunction Could Be a Cause of Heart Failure with Preserved Ejection Fraction Development in a Rat Model.Oxidative medicine and cellular longevity · 2022Article
- Mechanisms of decreased tubular flow-induced nitric oxide in Dahl salt-sensitive rat thick ascending limbs.American journal of physiology. Renal physiology · 2021Article
- Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2.Antioxidants (Basel, Switzerland) · 2021Article
- Chronic stress induced perivascular adipose tissue impairment of aortic function and the therapeutic effect of exercise.Experimental physiology · 2021Article
- Article
- Role of nitric oxide in mediating the cardioprotective effect of agomelatine against isoproterenol-induced myocardial injury in rats.Naunyn-Schmiedeberg's archives of pharmacology · 2020Article
- S-glutathionylation, friend or foe in cardiovascular health and disease.Redox biology · 2020Review
- Therapeutic Potential of Polyphenols-Loaded Polymeric Nanoparticles in Cardiovascular System.Molecules (Basel, Switzerland) · 2020Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGlutathionylation of endothelial nitric oxide synthase (eNOS) "uncouples" the enzyme, switching its function from nitric oxide (NO) to O2(•-) generation. We examined whether this reversible redox modification plays a role in angiotensin II (Ang II)-induced endothelial dysfunction. METHODS AND
resultsAng II increased eNOS glutathionylation in cultured human umbilical vein endothelial cells (HUVECs), rabbit aorta, and human arteries in vitro. This was associated with decreased NO bioavailability and eNOS activity as well as increased O2(•-) generation. Ang II-induced decrease in eNOS activity was mediated by glutathionylation, as shown by restoration of function by glutaredoxin-1. Moreover, Ang II-induced increase in O2(•-) and decrease in NO were abolished in HUVECs transiently transfected, with mutant eNOS rendered resistant to glutathionylation. Ang II effects were nicotinamide adenine dinucleotide phosphate (NADPH) oxidase dependent because preincubation with gp 91ds-tat, an inhibitor of NADPH oxidase, abolished the increase in eNOS glutathionylation and loss of eNOS activity. Functional significance of glutathionylation in intact vessels was supported by Ang II-induced impairment of endothelium-dependent vasorelaxation that was abolished by the disulfide reducing agent, dithiothreitol. Furthermore, attenuation of Ang II signaling in vivo by administration of an angiotensin converting enzyme (ACE) inhibitor reduced eNOS glutathionylation, increased NO, diminished O2(•-), improved endothelium-dependent vasorelaxation and reduced blood pressure.
conclusionsUncoupling of eNOS by glutathionylation is a key mediator of Ang II-induced endothelial dysfunction, and its reversal is a mechanism for cardiovascular protection by ACE inhibition. We suggest that Ang II-induced O2(•-) generation in endothelial cells, although dependent on NADPH oxidase, is amplified by glutathionylation-dependent eNOS uncoupling.
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