ArticleJournal of thrombosis and haemostasis : JTH2023
Sulfenylation links oxidative stress to protein disulfide isomerase oxidase activity and thrombus formation.
Article in Journal of thrombosis and haemostasis : JTH, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 28 citations in OpenAlex.
- Article
- Olfactory Receptor Activation Reduces Platelet Reactivity and Arterial Thrombosis Through Actin Cytoskeleton Remodeling.Circulation · 2026Article
- Defining and refining the cysteine redoxome through sulfur chemical biology.Nature chemical biology · 2026Review
- A mechanism for the disrupted redox regulation of vascular contractility during aging.iScience · 2026Article
- Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.Biochemistry · 2026Review
- Assays of Thiol Isomerase Activity.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Thiol Isomerases: Enzymatic Mechanisms, Models of Oxidation, and Antagonism by Galloylated Polyphenols.Antioxidants (Basel, Switzerland) · 2025Review
- Allosteric Disulfide Bridges in Integrins: The Molecular Switches of Redox Regulation of Integrin-Mediated Cell Functions.Antioxidants (Basel, Switzerland) · 2025Review
- Extracellular PDI in thrombosis and vascular injury.Thrombosis journal · 2025Review
- Galloylated polyphenols represent a new class of antithrombotic agents with broad activity against thiol isomerases.Journal of thrombosis and haemostasis : JTH · 2025Article
- Platelets welcome a new protein disulfide isomerase family member.Journal of thrombosis and haemostasis : JTH · 2025Article
- Recent advances in vascular thiol isomerases and redox systems in platelet function and thrombosis.Journal of thrombosis and haemostasis : JTH · 2024Review
- Effect of reactive oxygen, nitrogen, and sulfur species on signaling pathways in atherosclerosis.Vascular pharmacology · 2024Review
- Targeting Cysteine Oxidation in Thrombotic Disorders.Antioxidants (Basel, Switzerland) · 2024Review
- Platelet proteo-transcriptomic profiling validates mediators of thrombosis and proteostasis in patients with myeloproliferative neoplasms.bioRxiv : the preprint server for biology · 2023Article
- Cysteine and methionine oxidation in thrombotic disorders.Current opinion in chemical biology · 2023Review
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13 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundOxidative stress contributes to thrombosis in atherosclerosis, inflammation, infection, aging, and malignancy. Oxidant-induced cysteine modifications, including sulfenylation, can act as a redox-sensitive switch that controls protein function. Protein disulfide isomerase (PDI) is a prothrombotic enzyme with exquisitely redox-sensitive active-site cysteines.
objectivesWe hypothesized that PDI is sulfenylated during oxidative stress, contributing to the prothrombotic potential of PDI.
methodsBiochemical and enzymatic assays using purified proteins, platelet and endothelial cell assays, and in vivo murine thrombosis studies were used to evaluate the role of oxidative stress in PDI sulfenylation and prothrombotic activity.
resultsPDI exposure to oxidants resulted in the loss of PDI reductase activity and simultaneously promoted sulfenylated PDI generation. Following exposure to oxidants, sulfenylated PDI spontaneously converted to disulfided PDI. PDI oxidized in this manner was able to transfer disulfides to protein substrates. Inhibition of sulfenylation impaired disulfide formation by oxidants, indicating that sulfenylation is an intermediate during PDI oxidation. Agonist-induced activation of platelets and endothelium resulted in the release of sulfenylated PDI. PDI was also sulfenylated by oxidized low-density lipoprotein (oxLDL). In an in vivo model of thrombus formation, oxLDL markedly promoted platelet accumulation following an arteriolar injury. PDI oxidoreductase inhibition blocked oxLDL-mediated augmentation of thrombosis.
conclusionPDI sulfenylation is a critical posttranslational modification that is an intermediate during disulfide PDI formation in the setting of oxidative stress. Oxidants generated by vascular cells during activation promote PDI sulfenylation, and interference with PDI during oxidative stress impairs thrombus formation.
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