Inflammatory response and the endothelium

Meroni, Pier Luigi; Borghi, Maria Orietta; Raschi, Elena; Ventura, Donatella; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola; Lonati, Laura; Parati, Gianfranco; Tincani, Anǵela; Mari, Daniela; Tedesco, Francesco

doi:10.1016/j.thromres.2004.06.045

Cited by 69 publications

(49 citation statements)

References 42 publications

(51 reference statements)

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“…Thrombus formation was significantly reduced or abrogated in mice lacking the leukocyte adhesion molecules ICAM-1, E-selectin or P-selectin or by injection with anti-VCAM-1 antibodies [12,13]. These results imply that activation of the vascular endothelium by aPLA is a major thrombogenic mechanism [14]. Several in vitro as well as in vivo studies have shown that aPLA may recognize target antigens, such as β2GP1, bound to the surface of EC [15].…”

Section: Cell Activation By Aplamentioning

confidence: 83%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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Section: Cell Activation By Aplamentioning

confidence: 83%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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“…However, the presence of aPL and aPL actions on endothelium are not sufficient, because most of the time patients with circulating aPL do not have thromboses. A "two-hit hypothesis" has been proposed in which aPL (the first hit) induces a threshold cellular perturbation in endothelium, or possibly in platelets, and another condition (the second hit) is required to trigger actual clot formation (60). In most prior stud-…”

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.

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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“…Statin therapy not only has a beneficial effect on lipid profile, but also improves endothelial function, enhances the stability of atherosclerotic plaques, decreases oxidative stress and inflammation, and inhibits thrombogenic response [58]. Statins may also reduce an anti-β2GPI-induced proadhesive and proinflammatory endothelial phenotype [59]. Hydroxychloroquine has been reported to exert antiatherogenic properties [60], however, its effects need to be clinically confirmed [54].…”

Section: Accelerated Atherosclerosis In Apsmentioning

confidence: 99%