ArticleThe Journal of biological chemistry2016
Thioredoxin Uses a GSH-independent Route to Deglutathionylate Endothelial Nitric-oxide Synthase and Protect against Myocardial Infarction.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Molecular Mechanisms Governing Vascular Function in Heart Failure.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Redox Regulation of KAntioxidants & redox signaling · 2024Review
- Oxidative stress and the role of redox signalling in chronic kidney disease.Nature reviews. Nephrology · 2024Review
- Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets.Cellular & molecular biology letters · 2023Article
- Relationships between the Reversible Oxidation of the Single Cysteine Residue and the Physiological Function of the Mitochondrial Glutaredoxin S15 fromAntioxidants (Basel, Switzerland) · 2022Article
- Systemic and Renal Dynamics of Free Sulfhydryl Groups during Living Donor Kidney Transplantation.International journal of molecular sciences · 2022Article
- Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target.International journal of molecular sciences · 2021Review
- Chaperone-Mediated Autophagy of eNOS in Myocardial Ischemia-Reperfusion Injury.Circulation research · 2021Article
- Nrg1β Released in Remote Ischemic Preconditioning Improves Myocardial Perfusion and Decreases Ischemia/Reperfusion Injury via ErbB2-Mediated Rescue of Endothelial Nitric Oxide Synthase and Abrogation of Trx2 Autophagy.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
- Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation.Molecules (Basel, Switzerland) · 2021Review
- Calcium Ionophore-Induced Extracellular Vesicles Mediate Cytoprotection against Simulated Ischemia/Reperfusion Injury in Cardiomyocyte-Derived Cell Lines by Inducing Heme Oxygenase 1.International journal of molecular sciences · 2020Article
- Redox Regulation of STAT1 and STAT3 Signaling.International journal of molecular sciences · 2020Review
- Endothelial cell-cardiomyocyte crosstalk in heart development and disease.The Journal of physiology · 2020Review
- Dysregulation of the glutaredoxin/American journal of physiology. Cell physiology · 2020Article
- Rapid free thiol rebound is a physiological response following cold-induced vasoconstriction in healthy humans, primary Raynaud and systemic sclerosis.Physiological reports · 2019Article
- Thioredoxin and glutaredoxin regulate metabolism through different multiplex thiol switches.Redox biology · 2019Article
- ReversibleThe Journal of biological chemistry · 2019Article
- Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their RegulationPhysiological reviews · 2019Review
- Structural and Biochemical Insights into the Reactivity of Thioredoxin h1 fromAntioxidants (Basel, Switzerland) · 2019Article
- Role of Thioredoxin in Age-Related Hypertension.Current hypertension reports · 2018Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Reversible glutathionylation plays a critical role in protecting protein function under conditions of oxidative stress generally and for endothelial nitric-oxide synthase (eNOS) specifically. Glutathione-dependent glutaredoxin-mediated deglutathionylation of eNOS has been shown to confer protection in a model of heart damage termed ischemia-reperfusion injury, motivating further study of eNOS deglutathionylation in general. In this report, we present evidence for an alternative mechanism of deglutathionylation. In this pathway thioredoxin (Trx), a small cellular redox protein, is shown to rescue eNOS from glutathionylation during ischemia-reperfusion in a GSH-independent manner. By comparing mice with global overexpression of Trx and mice with cardiomyocyte-specific overexpression of Trx, we demonstrate that vascular Trx-mediated deglutathionylation of eNOS protects against ischemia-reperfusion-mediated myocardial infarction. Trx deficiency in endothelial cells promoted eNOS glutathionylation and reduced its enzymatic activity, whereas increased levels of Trx led to deglutathionylated eNOS. Thioredoxin-mediated deglutathionylation of eNOS in the coronary artery in vivo protected against reperfusion injury, even in the presence of normal levels of GSH. We further show that Trx directly interacts with eNOS, and we confirmed that Cys-691 and Cys-910 are the glutathionylated sites, as mutation of these cysteines partially rescued the decrease in eNOS activity, whereas mutation of a distal site, Cys-384, did not. Collectively, this study shows for the first time that Trx is a potent deglutathionylating protein in vivo and in vitro that can deglutathionylate proteins in the presence of high levels of GSSG in conditions of oxidative stress.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.