ArticleCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology2021
Extracellular Histones Bind Vascular Glycosaminoglycans and Inhibit the Anti-Inflammatory Function of Antithrombin.
Article in Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Emerging biomodels to understand the pathophysiology of sepsis and evaluate new therapeutic strategies targeting extracellular histones.Materials today. Bio · 2026Review
- Extracellular vesicles as emerging platforms for modulating innate immune responses in sepsis-associated acute lung injury.Frontiers in immunology · 2026Review
- Disseminated intravascular coagulation.Journal of intensive care · 2025Review
- Physiological significance of antithrombin D-helix interaction with vascular GAGs.Blood advances · 2025Article
- Antithrombin regulates neutrophil activities through the stimulation of C-type lectin family 1A.Blood vessels, thrombosis & hemostasis · 2025Article
- Thrombomodulin Switches Signaling and Protease-Activated Receptor 1 Cleavage Specificity of Thrombin.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review.Frontiers in immunology · 2024Review
- Coagulation Disorders in Sepsis and COVID-19-Two Sides of the Same Coin? A Review of Inflammation-Coagulation Crosstalk in Bacterial Sepsis and COVID-19.Journal of clinical medicine · 2023Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND/
aimsBinding of histones to molecular pattern recognition receptors on endothelial cells and leukocytes provokes proinflammatory responses and promotes activation of coagulation. Histones also bind therapeutic heparins, thereby neutralizing their anticoagulant functions. The aim of this study was to test the hypothesis that histones can interact with the antithrombin (AT)-binding vascular glycosaminoglycans (GAGs) to induce inflammation and inhibit the anti-inflammatory function of AT.
methodsWe evaluated the heparin-binding function of histones by an AT-dependent protease-inhibition assay. Furthermore, we treated endothelial cells with histones in the absence and presence of AT and monitored cellular phenotypes employing established signaling assays.
resultsHistones neutralized AT-dependent anticoagulant function of heparin in both purified protease-inhibition and plasma-based assays. Histones also disrupted endothelial cell barrier-permeability function by a GAG-dependent mechanism as evidenced by the GAG-antagonist, surfen, abrogating their disruptive effects. Further studies revealed histones and AT compete for overlapping binding-sites on GAGs, thus increasing concentrations of one protein abrogated effects of the other. Histones elicited proapoptotic effects by inducing nuclear localization of PKC-δ in endothelial cells and barrier-disruptive effects by destabilizing VE-cadherin, which were inhibited by AT, but not by a D-helix mutant of AT incapable of interacting with GAGs. Finally, histones induced release of Weibel-Palade body contents, VWF and angiopoietin-2, and promoted expression of cell adhesion molecules on endothelial cells, which were all downregulated by AT but not by D-helix mutant of AT.
conclusionWe conclude that histones and AT compete for overlapping binding sites on vascular GAGs to modulate coagulation and inflammation.
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Registered trials
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