Endothelial function is impaired in patients with primary antiphospholipid syndrome

Štalc, Monika; Poredoš, Pavel; Peternel, Polona; Tomšič, Matija; Šebeštjen, Miran; Kveder, T

doi:10.1016/j.thromres.2005.09.005

Cited by 43 publications

(33 citation statements)

References 33 publications

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“…These observations are consistent with the finding in APS patients that endothelium-dependent, NO-dependent flow-mediated dilation of the brachial artery is impaired, whereas endothelium-independent vasodilation is normal (48,49). In addition, in APS patients there is a negative correlation between flow-mediated dilation and circulating levels of the adhesion molecules VCAM-1 and ICAM-1 (48). Consistent with this inverse relationship between the capacity for NO production and the degree of vascular inflammation in APS patients, our work in both cultured endothelial cells and in vivo in mice now reveals a causal link between aPL-induced eNOS antagonism and increased leukocyte-endothelial cell adhesion.…”

Section: Discussionsupporting

confidence: 93%

“…Studies of carotid vascular conductance in mice also showed that aPL attenuate eNOS activation, demonstrating the physiologic importance of this effect in vivo. These observations are consistent with the finding in APS patients that endothelium-dependent, NO-dependent flow-mediated dilation of the brachial artery is impaired, whereas endothelium-independent vasodilation is normal (48,49). In addition, in APS patients there is a negative correlation between flow-mediated dilation and circulating levels of the adhesion molecules VCAM-1 and ICAM-1 (48).…”

Section: Discussionsupporting

confidence: 91%

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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.

176

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: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

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.

176

226

View full text Add to dashboard Cite

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“…The higher frequency of aPL in primary APS patients with MetS is of particular concern because these antibodies have a role in endothelial dysfunction (26), which may ultimately contribute to further amplify the accelerated atherosclerosis and thromboembolic complications present in these patients due to MetS (29). In this regard, 2 studies suggested that LAC is a major risk factor for arterial thrombotic events in young women and aPL carriers (30,31), and 2 other studies reported that aPL was associated with higher risk of myocardial infarction (32,33) in an unselected population of young women.…”

Section: Discussionmentioning

confidence: 99%

Association of arterial events with the coexistence of metabolic syndrome and primary antiphospholipid syndrome

Rodrigues

Bonfá

Caleiro

et al. 2012

Arthritis Care & Research

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Objective. Metabolic syndrome (MetS) is highly prevalent in rheumatic diseases and is recognized as a new independent cardiovascular risk factor. This study was undertaken to determine the clinical significance of MetS in patients with primary antiphospholipid syndrome (APS). Methods. Seventy-one primary APS patients and 73 age-and sex-matched healthy controls were included. Serum samples were tested for lipid profile, Lp(a), glucose, insulin, thyroid-stimulating hormone, free T4, erythrocyte sedimentation rate, C-reactive protein level, and uric acid. MetS was defined by the International Diabetes Federation criteria, and insulin resistance was established using the homeostasis model assessment index. Results. The prevalence of MetS was 33.8%, and further comparison between primary APS patients with and withoutMetS revealed that the former had a higher frequency of arterial events (79.2% versus 42.6%; P ‫؍‬ 0.003), angina (29.2% versus 2.1%; P ‫؍‬ 0.002), and positive lupus anticoagulant antibody (95.8% versus 76.6%; P ‫؍‬ 0.049). In addition, primary APS patients with MetS, as expected, had a higher prevalence of cardiovascular risk factors. On multivariate analysis, only MetS was independently associated with arterial events in primary APS. Conclusion. Coexistence of primary APS and MetS seems to identify a subgroup of patients with higher risk of arterial events, suggesting that MetS may aggravate existing endothelial abnormalities of primary APS.

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“…The most popular theory to explain the prothrombotic action of aPL is the effect of these antibodies on different cell types [58][59][60][61][62][63][64][65][66][67][68]. It was originally thought that aPL were directed against anionic phospholipids, and therefore, it was logical to study the interaction of b 2 GPI with cellular membranes and cells.…”

mentioning

confidence: 99%

Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment

Tripodi

Groot

Pengo³

2011

Journal of Internal Medicine

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Abstract. Tripodi A, de Groot PG, Pengo V (IRCCS Cà Granda Ospedale Maggiore Policlinico Foundation and Università degli Studi di Milano, Milan, Italy; Utrecht University Medical Center, Utrecht, the Netherlands; Thrombosis Center, University Hospital, Padua, Italy). Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment (Review). J Intern Med 2011; 270: 110-122.The antiphospholipid syndrome (APS) identifies a condition at increased risk of vascular occlusion and ⁄ or pregnancy complications. Patients are defined as having APS if they have at least one clinical (vascular occlusion and ⁄ or pregnancy complications) and one laboratory criterion at the same time. The laboratory criteria that define APS are repeated positivity (confirmed 12 weeks apart) for lupus anticoagulants and ⁄ or antibodies targeted against cardiolipin or b 2 -glycoprotein I immobilized on solid surfaces. Over the years, APS has attracted the interest of many medical specialties. The aim of this review is to provide an update on (i) the laboratory criteria that determine the presence of APS, (ii) how the antibodies increase the risk of vascular occlusion and foetal loss and (iii) the treatment of the related clinical events.

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Endothelial function is impaired in patients with primary antiphospholipid syndrome

Cited by 43 publications

References 33 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

Association of arterial events with the coexistence of metabolic syndrome and primary antiphospholipid syndrome

Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment

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