Abstract
The high circulating levels of histones found in various thrombotic diseases may compromise the anticoagulant barrier of endothelial cells. We determined how histones affect endothelial procoagulant tissue factor (TF) and anticoagulant thrombomodulin (TM). Surface antigens, soluble forms, and mRNA levels of TF and TM were measured by flow cytometry, ELISA, and real-time RT-PCR, respectively. TF and TM activity were measured using procoagulant activity, thrombin generation, or chromogenic assays. Involvement of the toll-like receptor (TLR) was assessed using the neutralizing antibodies. Histones dose-dependently induced surface antigens, activity and mRNA levels of endothelial TF. Histone-treated endothelial cells significantly shortened the lag time and enhanced the endogenous thrombin potential of normal plasma, which was normalized by a TF neutralizing antibody. Histones induced phosphatidylserine and protein-disulfide isomerase expression in endothelial cells. Histones also reduced the surface antigen, activity, and mRNA levels of endothelial TM. Polysialic acid and heparin reversed the histone-induced TF up-regulation and TM down-regulation. Activated protein C did not affect the TF up-regulation, but interrupted TM down-regulation. TLR2, and TLR4 inhibitors partially blocked the TF up-regulation. Histones induced the endothelial procoagulant phenotype through TF up-regulation and TM down-regulation. The effects of histones were partly mediated by TLR2, TLR4. Strategies to inhibit the harmful effects of histones in endothelial cells may be required in order to prevent a thrombotic environment.
Highlights
Histones exist predominantly in a form of nucleosome associated with DNA within the cell nucleus
To investigate the relative effect of individual histones on tissue factor (TF) expression of endothelial cells, they were treated with each subtype of histones
Consistent with the results of the aforementioned report [30], our results demonstrated that protein-disulfide isomerase (PDI) inhibition increased TF activity and indicated that endothelial PDI is a negative regulator of TF activity
Summary
Histones exist predominantly in a form of nucleosome associated with DNA within the cell nucleus. In a phenomenon referred to as extracellular traps, histones can be released into the blood circulation by inflammatory stimuli from peripheral leukocytes, such as neutrophils, PLOS ONE | DOI:10.1371/journal.pone.0156763. Histones Induce Procoagulant Endothelium mast cells, eosinophils, and monocytes [1]. The extracellular traps are actively formed in patients with inflammatory, autoimmune, and thrombotic diseases [2,3,4,5]. The contribution of histones to the process of coagulation has received recent attention [6]. Histones induce platelet activation [7, 8] and enhance plasma thrombin formation via binding to protein C and thrombomodulin (TM) [9]
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