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Decreased binding of annexin V to endothelial cells: a novel mechanism of atherothrombosis in patients with systemic lupus erythematosus

Background

Patients with systemic lupus erythematosus (SLE) are at high risk of cardiovascular disease, due to atherothrombosis in particular. The mechanisms are not clear; however, recently annexin V, an anticoagulant protein, and antiphospholipid antibodies have been implicated.

Methods

Twenty-six women (52 ± 8.2 years) with SLE and a history of cardiovascular disease (SLE cases) were compared with two age-matched control groups: 26 women with SLE but no cardiovascular disease (SLE controls) and 26 healthy women (population controls). Common carotid intima-media thickness was determined by B-mode ultrasound as a surrogate measure of atherosclerosis. Annexin V binding to human umbilical vein endothelial cells was assessed by flow cytometry after 24-hour culture with plasma. The presence of annexin V in carotid atherosclerotic plaques was determined by immunohistochemistry. Annexin V levels in circulation and anti-annexin IgG and IgM antibodies were measured by a commercially available high-sensitivity ELISA. Pooled sera with high capacity to inhibit annexin V binding were preabsorbed against different concentrations of antigens such as cardiolipin and phosphorylcholine and against unrelated antigen tetanus toxoid. Annexin V-binding assay with flow cytometry was performed.

Results

Binding of annexin V was significantly lower when plasma from SLE cases was used as compared with controls (SLE cases versus population controls P = 0.002, SLE cases versus SLE controls P = 0.02). There was a striking positive association between annexin V binding and intima-media thickness (R = 0.73, P < 0.001) among SLE cases. The annexin V levels were increased in SLE cases compared with both SLE controls and PC (P = 0.03 and P = 0.004), but no differences were detected in anti-annexin V IgG or IgM levels. Depletion of IgG from sera with high capacity to inhibit binding of annexin V induced a 2.7-fold increase in binding and preincubation of sera with cardiolipin and phosphorylcholine resulted in increase of median fluorescence intensity of annexin V binding to human umbilical vein endothelial cells. Immunohistochemical analysis revealed the presence of annexin V in all plaques tested.

Conclusions

Decreased annexin V binding to endothelium caused by immunoglobulin may represent a novel mechanism of atherothrombosis. Increasing annexin V binding may thus represent a novel therapeutic possibility.

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Cederholm, A., Svenungsson, E., Jensen-Urstad, K. et al. Decreased binding of annexin V to endothelial cells: a novel mechanism of atherothrombosis in patients with systemic lupus erythematosus. Arthritis Res Ther 7, P143 (2005). https://doi.org/10.1186/ar1664

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Keywords

  • Systemic Lupus Erythematosus
  • Annexin Versus
  • Human Umbilical Vein Endothelial Cell
  • Phosphorylcholine
  • Median Fluorescence Intensity