Antiphospholipid Antibodies Activate Vascular Endothelial Cells

Simantov, Ronit; Sk, Lo; Gharavi, Azzudin E.; Sammaritano, L. R.; Salmon, JE; Silverstein, RL

doi:10.1177/096120339600500521

Cited by 51 publications

(37 citation statements)

References 11 publications

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“…Although direct actions of aPL on platelets are likely contributory to APS-related thrombosis, there is a major role for the activation of endothelial cell adhesion in aPL-induced thrombus formation (9,58,59). This has been most clearly indicated by studies demonstrating that ICAM1 -/-mice and mice administered anti-VCAM-1 monoclonal antibody are fully protected from aPLinduced thrombus formation (16).…”

Section: Discussionmentioning

confidence: 99%

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.

179

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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Section: Discussionmentioning

confidence: 99%

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.

179

226

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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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“…The adhesion molecules VCAM-1, ICAM-1 and E-sel have been shown to be upregulated in ECs activated by aPL [34,117,118]. Utilizing ICAM-1, VCAM-1, E-sel and P-selectin (P-sel) knockout mice, our group demonstrated the importance of ICAM-1, E-sel, P-sel and VCAM-1 in promoting leukocyte adhesion and thrombus formation mediated by human polyclonal and monoclonal aPL antibodies [91].…”

Section: Direct Proinflammatory and Prothrombotic Effects Of Antiphosmentioning

confidence: 80%

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

Pierangeli¹,

Harper²,

Harris³

2012

Antiphospholipid Syndrome

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Antiphospholipid Antibodies Activate Vascular Endothelial Cells

Cited by 51 publications

References 11 publications

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

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

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

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

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