Increased Expression of Inducible Cyclooxygenase-2 in Human Endothelial Cells by Antiphospholipid Antibodies

Habib, Aı̈da; Martinuzzo, Marta; Carreras, L; Lévy-Toledano, S; Maclouf, Jacques

doi:10.1055/s-0038-1649811

Cited by 17 publications

(9 citation statements)

References 29 publications

(39 reference statements)

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“…Our studies revealed that endothelial cells stimulated with antiendothelial cell antibodies and complement did indeed produce increased amounts of prostaglandins and thromboxane through the induction of Cox-2. However, in contrast to the effects in other systems (24), complement did not induce eicosanoid production directly; rather, complement induced the synthesis and secretion of IL-1␣, which acted on endothelial cells as an autocrine factor inducing the change in eicosanoid metabolism that ensue.…”

Section: Discussioncontrasting

confidence: 63%

Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Bustos

Coffman²,

Saadi³

et al. 1997

J. Clin. Invest.

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Lipid inflammatory mediators are thought to play a critical role in the pathogenesis of vascular injury. Among the events which might cause the synthesis of eicosanoids in blood vessels is activation of the complement. To evaluate how complement might influence eicosanoid metabolism, we investigated endothelial cells exposed to xenoreactive antibodies and complement, as might occur in rejecting xenografts where severe vascular injury is a typical feature. While resting porcine aortic endothelial cells released only prostaglandin (PG) I 2 , endothelial cells stimulated with xenoreactive antibodies and complement released PGE 2 and thromboxane A 2 (TXA 2 ), in addition to increased amounts of PGI 2 . This alteration in eicosanoid metabolism was associated with induction of cyclooxygenase (Cox)-2 and thromboxane synthase, but not Cox-1. Unlike results seen in other systems, the upregulation of Cox-2 and the subsequent release of eicosanoids by endothelial cells was not directly induced by complement but rather required production of IL-1 ␣ , which acted on endothelial cells as an autocrine factor. Since eicosanoids have a potent effect on inflammation, vascular tone and platelet aggregation, we postulated that the abnormalities in eicosanoid release induced by xenoreactive antibodies and complement might provide one explanation for the vascular injury, focal ischemia, and thrombosis observed in acute vascular rejection and other vasculitides mediated by complement. ( J.

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Section: Discussioncontrasting

confidence: 63%

Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Bustos

Coffman²,

Saadi³

et al. 1997

J. Clin. Invest.

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“…In patients with APS, levels of the urinary metabolites of prostacyclin are strongly elevated [26]. Furthermore, in cultured EC, APLA increase the formation of 6-keto-PGF 1a , the main metabolite of prostacyclin [26]. Our finding that aspirin inhibits the APLAmediated increase in VCAM-1 protein and mRNA suggests that the activation of COX activity is a major factor in the activation of EC by APLA.…”

Section: Discussionmentioning

confidence: 67%

“…There is some evidence that APLA increase COX activity in vivo. In patients with APS, levels of the urinary metabolites of prostacyclin are strongly elevated [26]. Furthermore, in cultured EC, APLA increase the formation of 6-keto-PGF 1a , the main metabolite of prostacyclin [26].…”

Section: Discussionmentioning

confidence: 98%

“…It is also possible that part of the effect of aspirin on thrombosis prophylaxis in APLA patients relies on platelet thromboxane inhibition. It has been shown that the urine of APLA patients has increased quantities of thromboxane metabolites [26,27] and that purified APLA increase platelet thromboxane production after minimal thrombin stimulation in vitro [28]. However, the ability of APLA to activate platelets directly is still debated, since, for example, incubation with APS sera resulted in an increase of platelet-associated IgG without any clear activation in one study [29].…”

Section: Discussionmentioning

confidence: 99%

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Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies

Dunoyer‐Geindre

Kruithof

Boehlen

et al. 2004

Journal of Thrombosis and Haemostasis

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Summary. Background: Antiphospholipid antibodies (APLA) have been shown to activate endothelial cells (EC) in vitro, as documented by an increased expression of tissue factor as well as leukocyte adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin. Currently, treatment of patients with the antiphospholipid syndrome includes aspirin, particularly for women with recurrent fetal loss. Objective: The present study was undertaken to investigate whether aspirin interferes with EC activation induced by APLA in vitro. Methods: IgG from 14 patients with APLA, and suffering from thrombotic complications and/or pregnancy morbidity, and control IgG were tested for their ability to modify the expression of VCAM-1 in human umbilical vein endothelial cells. VCAM-1 antigen was measured by flow cytometry and its mRNA by quantitative reverse transcriptase-polymerase chain reaction. Results: Incubation of EC with IgG from most of the patients led to a higher VCAM-1 expression compared with incubation with control IgG. The effect of aspirin was studied for the eight IgG samples that induced a more than 50% increase in VCAM-1. Aspirin (10 mM) treatment of the cells significantly reduced the VCAM-1 response to these APLA. Conclusions: Our results indicate that besides its antiplatelet properties, aspirin exerts a protective effect towards APLA at the EC level by decreasing leukocyte adhesion molecule expression at the cell surface.

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“…Our current data extend that finding and provide further evidence that flares of SLE are accompanied by the widespread activation of the endothelium, making these cells potential participants in the inflammatory processes which contribute to tissue injury. Potential immune stimuli which may account for endothelial cell activation in SLE include immune complexes, complement components (e.g., CSa, C5b-9, C1 q), antiendothelial cell antibodies, and anticardiolipin antibodies, as well as cytokines such as interleukin-1 (IL-1) or tumor necrosis factor (15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

Increased nitric oxide production accompanied by the up‐regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus

Levartovsky

Goel

et al. 1997

Arthritis & Rheumatism

145

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Objective. To investigate whether systemic lupus erythematosus (SLE) is accompanied by increased serum nitrite levels, whether active compared with inactive disease is associated with greater nitric oxide (NO) production, and whether endothelial cells or keratinocytes serve as cellular sources of NO by virtue of their increased expression of either constitutive nitric oxide synthase (cNOS) or inducible NOS (iNOS).Methods. Fifty-one serum samples (46 from patients with SLE) were analyzed for NO production by measuring nitrite levels in a calorimetric assay. Skin biopsy samples from 21 SLE patients and 11 healthy volunteers were evaluated immunohistochemically, using monoclonal antibodies, for endothelial cell and keratinocyte cNOS and iNOS expression.Results. Serum nitrite levels were significantly elevated in the 46 patients with SLE (mean & SEM 37 & 6 pM/liter) compared with controls (15 & 7 pM/liter; P < 0.01), and were eleyated in patients with active SLE compared with those with inactive disease (46 2 7 pM/liter versus 30 e 7 pM/liter; P < 0.01). Serum nitrite levels correlated with disease activity (r = 0.47, P = 0.04) and with levels of antibodies to doublestranded DNA (r = 0.35, P = 0.02). Endothelial cell expression of iNOS in SLE patients (mean & SEM score 1.5 e 0.2) was significantly greater compared with controls (0.6 e 0.2; P < 0.01), and higher in patients €1.

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Increased Expression of Inducible Cyclooxygenase-2 in Human Endothelial Cells by Antiphospholipid Antibodies

Cited by 17 publications

References 29 publications

Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies

Increased nitric oxide production accompanied by the up‐regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus

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