Tissue factor in the antiphospholipid syndrome

Kinev, Alexander; Roubey, Robert

doi:10.1177/0961203308096662

Cited by 44 publications

(25 citation statements)

References 92 publications

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“…We hypothesize that this initial event involves, at least in part, the activation of endothelial cells, leading to increased expression of cell surface adhesion molecules that promote monocyte and platelet adhesion, 11,38 the elaboration of microparticles, [38][39][40] and the expression of tissue factor. 41,42 Support for this hypothesis is supported by studies demonstrating that anti-␤ 2 GPI antibodies activate endothelial cells in a ␤ 2 GPIdependent manner 11 and that elevated levels of endothelial cell and platelet-derived microparticles circulate in patients with APLA/anti-␤ 2 GPI antibodies, even in the absence of an acute thrombotic event. 11,38,40,43 Defining the molecular pathways that facilitate vascular cell activation in patients with these antibodies may provide additional insight into disease pathogenesis and potentially suggest new directions for more specific therapeutic intervention than indefinite anticoagulation.…”

Section: Discussionmentioning

confidence: 52%

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Allen

Hamik

Jain

et al. 2011

Blood

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IntroductionThe antiphospholipid syndrome (APS) is characterized by arterial or venous thrombosis and/or recurrent fetal loss in the presence of antiphospholipid antibodies (APLAs). [1][2][3] It is now widely accepted that the majority of pathologic antibodies in patients with this disorder are actually directed against phospholipid-binding proteins, the most common of which is ␤ 2 -glycoprotein I (␤ 2 GPI).The pathogenesis of APS-associated thrombosis is multifactorial, and a number of mechanisms have been proposed. 4 These include inhibition of protein C activation and activity, 5,6 inhibition of annexin V assembly on exposed phospholipid surfaces, 7 and prevention of appropriate interactions of antithrombin with glycosaminoglycans, 8 among others. 4,9 Studies from our laboratory and others suggest that ␤ 2 GPI-dependent activation of vascular cells by APLA/anti-␤ 2 GPI antibodies plays a central role in disease pathogenesis 10,11 and may initiate the cascade of events that leads to thrombus development. For example, ␤ 2 GPI binds to endothelial cell annexin A2, and subsequent cross-linking of annexin A2-bound ␤ 2 GPI initiates endothelial cell activation through a pathway that may involve Toll-like receptor 4 (TLR-4) [11][12][13] and leads to activation of NF-B. 14 A similar pathway may be functional in monocytes, activation of which also contributes to the development of thrombosis in patients with APLA. 15 In addition, APLA may promote platelet activation in the presence of subthreshold concentrations of agonists, 16 although whether this is a receptor-mediated process, and if so, its relationship to platelet ␤ 2 GPI binding sites, such as GP1b 17 and apoER2, 18 requires further study.In endothelial cells, activation of NF-B stimulates an inflammatory and procoagulant response 19 and plays a critical role in the ability of APLA to promote thrombosis. 20 Thus, modulation of NF-B activity may provide an opportunity to reverse the pathologic vascular response in APS. The Krüppel-like factors (KLFs), 21 particularly KLF2 and KLF4, inhibit inflammatory cytokinemediated responses in endothelial cells, 22,23 at least in part through inhibition of NF-B activity. 23 However, expression of KLF2 itself may be inhibited by inflammatory cytokines and/or vascular injury, [23][24][25] although the expression of KLF4 appears to be increased under these conditions. 26 In considering the importance of NF-B in endothelial cell activation mediated by APLA/anti-␤ 2 GPI antibodies 14 and the potentially opposing effects of KLF2 and KLF4, we hypothesized that changes in expression of these transcription factors might influence the endothelial cell response to APLA/anti-␤ 2 GPI antibodies. Here, we report that, unlike responses to inflammatory cytokines, the expression of both KLF2 and KLF4 is decreased in response to APLA/anti-␤ 2 GPI antibodies. Moreover, restoring the expression of these KLFs blocks endothelial cell activation in response to APLA/anti-␤ 2 GPI antibodies. These activities result from inhibition of NF-B transcrip...

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Section: Discussionmentioning

confidence: 52%

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Allen

Hamik

Jain

et al. 2011

Blood

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“…The proximal processes by which aPL cause changes in endothelial cell behavior have been elusive (52)(53)(54)63). We now provide multiple lines of evidence demonstrating that aPL-induced increases in leukocyte-endothelial cell adhesion and thrombus formation are caused by eNOS antagonism, which is due to impaired S1179 phosphorylation mediated by β2GPI, apoER2, and PP2A.…”

Section: Figurementioning

confidence: 85%

Antiphospholipid antibodies promote leukocyte–endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2

Ramesh¹,

Morrell²,

Tarango³

et al. 2011

J. Clin. Invest.

175

226

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In antiphospholipid syndrome (APS), antiphospholipid antibodies (aPL) binding to β2 glycoprotein I (β2GPI) induce endothelial cell-leukocyte adhesion and thrombus formation via unknown mechanisms. Here we show that in mice both of these processes are caused by the inhibition of eNOS. In studies of cultured human, bovine, and mouse endothelial cells, the promotion of monocyte adhesion by aPL entailed decreased bioavailable NO, and aPL fully antagonized eNOS activation by diverse agonists. Similarly, NO-dependent, acetylcholine-induced increases in carotid vascular conductance were impaired in aPL-treated mice. The inhibition of eNOS was caused by antibody recognition of domain I of β2GPI and β2GPI dimerization, and it was due to attenuated eNOS S1179 phosphorylation mediated by protein phosphatase 2A (PP2A). Furthermore, LDL receptor family member antagonism with receptor-associated protein (RAP) prevented aPL inhibition of eNOS in cell culture, and ApoER2 -/-mice were protected from aPL inhibition of eNOS in vivo. Moreover, both aPL-induced increases in leukocyte-endothelial cell adhesion and thrombus formation were absent in eNOS -/-and in ApoER2 -/-mice. Thus, aPL-induced leukocyte-endothelial cell adhesion and thrombosis are caused by eNOS antagonism, which is due to impaired S1179 phosphorylation mediated by β2GPI, apoER2, and PP2A. Our results suggest that novel therapies for APS can now be developed targeting these mechanisms.

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“…Anti-ß 2 GPI antibodies are found frequently in the plasma of patients, suggesting their important roles in APS. Growing evidences suggest that anti-ß 2 GPI antibodies stimulate blood cells and vascular endothelium to express tissue factor (TF) activity and exert procoagulant effects (6,7).…”

Section: Introductionmentioning

confidence: 99%

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

Zhou¹

2009

Int J Mol Med

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Abstract. Growing evidence suggests that autoantibodies directly contribute to hypercoagulability in the antiphospholipid syndrome (APS). One proposed mechanism is the antibodyinduced expression of tissue factor (TF) by blood monocytes. Annexin A2 (ANX2), a mediator of cell surface-specific plasmin generation, was identified to mediate endothelial cell activation by anti-ß 2 -glycoprotein I (anti-ß 2 GPI) antibody. Our previous study suggested that ANX2 was also involved in anti-ß 2 GPI/ß 2 GPI-induced TF expression on monocytes. In the current study, it was further demonstrated that ß 2 GPI interacts with ANX2 not only in a cell-dependent form but also in a cell-free system. To further confirm the effects of ANX2 on anti-ß 2 GPI/ß 2 GPI-induced TF expression, an ANX2 cDNAcontaining vector was transfected into HEK 293T cells which had originally little ANX2, then cells were treated by anti-ß 2 GPI/ß 2 GPI complex. It was found that transfected HEK 293T cells could express more TF both at mRNA and protein levels than that of no-transfected cells. On the other hand, the TF expression was dramatically decreased in the THP-1 cells in which the ANX2 RNA interference was performed. In conclusion, these results indicate that ANX2 on cell surface functions as a mediator boosting TF expression on monocytes induced by anti-ß 2 GPI/ß 2 GPI complex, which is contributed to the thrombotic events in APS.

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Tissue factor in the antiphospholipid syndrome

Cited by 44 publications

References 92 publications

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Antiphospholipid antibodies promote leukocyte–endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

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