Factor XIII mediates adhesion of platelets to endothelial cells through αvβ3 and glycoprotein IIb/IIIa integrins

Dardik, Rima; Шенкман, Борис; Tamarin, Ilia; Eskaraev, Regina; Hársfalvi, Jolán; Varon, David; Inbal, Aida

doi:10.1016/s0049-3848(02)00014-2

Cited by 44 publications

(44 citation statements)

References 19 publications

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“…The independence of transglutaminase activity is in line with our previous results [10] and the results of the present study. These data also confirm our previous observation that FXIII can bind directly to platelets [23]. However, in another study, we showed that PDI-dependent platelet adhesion is specific to platelet integrin-mediated adhesion [12,13].…”

Section: Discussionsupporting

confidence: 92%

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity

Lahav

Tvito

Bagoly

et al. 2013

Thrombosis Research

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Background: Factor XIII (FXIII), a plasma pro-transglutaminase, consists of two A subunits and two B subunits (FXIIIA2B2). Following activation by thrombin, it cross-links fibrin chains at the final step of coagulation. We previously reported that FXIII subunit A (FXIIIA) serves as a protein disulfide isomerase (PDI), and that PDI promotes platelet adhesion and aggregation. Objective: This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. Methods: Ex vivo experiments: Blood platelets derived from five patients with hereditary FXIIIA deficiency before and after treatment with Fibrogammin-P (FXIIIA2B2 concentrate) were washed and incubated on immobilized fibrinogen. Bound platelets were stained and counted by microscopy. In vitro experiments: Platelets derived from patients before treatment and five healthy controls were washed and analyzed for adhesion in the presence or absence of Fibrogammin-P or recombinant FXIII (FXIIIA2 concentrate). Results: In ex vivo experiments, one hour after Fibrogammin-P treatment, mean (±SEM) platelet adhesion to fibrinogen increased by 27±2.32% (pb 0.001). In in vitro experiments, treatment with Fibrogammin-P or recombinant FXIII (10 IU/mL each) enhanced platelet adhesion to fibrinogen (in patients, by 29.95±6.7% and 29.05±5.3%, respectively; in controls, by 26.06±3.24% and 26.91±4.72, respectively; pb 0.04 for all). Iodoacetamide-treated FXIII (I-FXIII), where transglutaminase activity is blocked, showed similar enhanced adhesion as untreated FXIII. By contrast, addition of an antibody that specifically blocks FXIIIA-PDI activity inhibited FXIII-mediated platelet adhesion to fibrinogen by 65%. Conclusion: These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.© 2012 Elsevier Ltd. All rights reserved. IntroductionCoagulation factor XIII (FXIII) is a plasma pro-transglutaminase. Following activation by thrombin, it cross-links fibrin chains at the final step of coagulation to form a soluble clot [1]. FXIII circulates in plasma as a heterotetramer of two A subunits (FXIIIA2 -the active transglutaminase) and two B subunits (FXIIIB2 -the carrier protein) [1]. Besides its role in hemostasis, FXIII accelerates wound healing [2], probably by its pro-angiogenic effects [3] as well as by stimulation of monocytes and fibroblasts [4]. Several new lines of evidence point to the involvement of FXIII in platelet function as well [5][6][7][8]. FXIII subunit A (FXIIIA) was detected on thrombin-receptor-activated platelets [5], and platelets were found to adhere to FXIII-covered surface [6]; this interaction depended on the intact fibrinogen binding to integrin αIIbβ3 [5,6]. Accordingly, no clot retraction was noted in FXIIIA knock-out mice [7], and patients with FXIII deficiency, a rare hereditary life-long bleeding disorder [8], showed reduced fibrinogen binding to thrombin-stimulated platelets and reduced platelet adhesion to fibrinogen-covered surface ...

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Section: Discussionsupporting

confidence: 92%

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity

Lahav

Tvito

Bagoly

et al. 2013

Thrombosis Research

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“…However, the movement of secreted endogenous TG isoenzymes to the cell surface is likely to be more efficient than for exogenous TGs. It should be noted that this study employed both catalytically active and inactive sFXIIIA at a concentration 500 times lower than the 50 μg/ml amounts of sFXIIIa previously added to vascular cells and fibroblasts (Dardik et al, 2002;Dardik et al, 2005;Dardik et al, 2007). We assessed changes in mutant FXIIIA TG catalytic activity in response to thrombin, but we did not investigate effects of the P37A and M513G mutations on endoproteolytic cleavage of FXIIIA by either thrombin alone or by chondrocytes without exogenous thrombin.…”

Section: Discussionmentioning

confidence: 99%

“…In fibroblasts, TG2 can bind to the extracellular domain of β1-and β3-integrin subunits (Akimov et al, 2000). Activated FXIIIA can bind to αVβ3 integrin in HUVECs (Dardik et al, 2002). Chondrocytes themselves express multiple integrins, including α1β1, α2β1, α5β1, α6β1, α10β1 and αVβ3 (Loeser, 2000).…”

Section: Fxiiia Induces P38 Mapk Signaling Dependent On Rapid Externamentioning

confidence: 99%

“…FXIIIA, similar to TG2, exerts both transamidation-dependent and transamidation-independent activities, binds integrins and functions to modulate both cell adhesion and differentiation. Seminal work by Dardik and colleagues has revealed that FXIIIA binds αVβ1 and αVβ3 integrins and has the potential to covalently and noncovalently complex them with other receptors, exemplified by vascular endothelial growth factor receptor 2 (VGFR2, hereafter referred to as VEGFR-2) (Dardik et al, 2002;Dardik et al, 2005;Dardik et al, 2007). Moreover, provision to monocytes and endothelial cells of catalytically active FXIIIA (FXIIIa) modulates cell signaling and impacts on functions such as angiogenesis, migration and apoptosis (Dardik et al, 2005;Dardik et al, 2007).…”

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confidence: 99%

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Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation

Johnson

Rose

Terkeltaub

2008

Journal of Cell Science

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Two transglutaminases (TGs), factor XIIIA (FXIIIA) and TG2, undergo physiologic upregulation in growth plate hypertrophic chondrocytes, and pathological upregulation in osteoarthritic cartilage. Externalization of guanine-nucleotide-bound TG2 drives chondrocyte maturation to hypertrophy, a state linked to matrix remodeling and calcification. Here, we tested the hypothesis that FXIIIA also promotes hypertrophic differentiation. Using human articular chondrocytes, we determined that extracellular FXIIIA induced chondrocyte hypertrophy associated with rapid movement of TG2 to the cell surface. Site-directed mutagenesis revealed that FXIIIA Pro37 bordering the thrombin endoproteolytic Arg38-Gly39 site, but not intrinsic TG catalytic activity, were necessary for FXIIIA to induce chondrocyte hypertrophy. TGs have been demonstrated to interact with certain integrins and, during osteoarthritis (OA), α1β1 integrin is upregulated and associated with hypertrophic chondrocytes. FXIIIA engaged α1β1 integrin in chondrocytes. Antibody crosslinking of α1β1 integrin mobilized TG2. Conversely, an α1β1-integrin-specific blocking antibody inhibited the capacity of FXIIIA to induce TG2 mobilization to the cell surface, phosphorylation of p38 MAP kinase, and chondrocyte hypertrophy. Our results identify a unique functional network between two cartilage TG isoenzymes that accelerates chondrocyte maturation without requirement for TG-catalyzed transamidation by either TG.

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“…For example, factor XIIIa supports the adhesion of platelets to endothelial cells. Factor XIIIa binds to endothelial cells via the alpha v beta 3 integrin and to platelets via GPIIb/IIIa (37)(38)(39)(40). Conceivably, intrinsic platelet transglutaminase activity serves to counterbalance platelet-derived matrix metalloproteinase activity.…”

Section: Transglutaminases and Platelet Functionmentioning

confidence: 99%

Roles of transglutaminases in cardiac and vascular diseases

Sane

Kontos²,

Greenberg³

2007

Front Biosci

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All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

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Factor XIII mediates adhesion of platelets to endothelial cells through αvβ3 and glycoprotein IIb/IIIa integrins

Cited by 44 publications

References 19 publications

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity

Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation

Roles of transglutaminases in cardiac and vascular diseases

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