期刊
CELLS
卷 11, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/cells11081288
关键词
antiphospholipid syndrome; beta 2-GPI-glycoprotein I; LRP-6; Tissue Factor; signal transduction
类别
This study analyzed the induction of Tissue Factor (TF) expression in endothelial cells by anti-beta 2-GPI antibodies from patients with APS through a LRP6 signal transduction pathway involving lipid rafts. The results showed that the anti-beta 2-GPI antibodies triggered LRP6 phosphorylation and subsequent activation of beta-catenin, leading to TF expression on the cell surface.
In this study we analyzed whether anti-beta 2-GPI antibodies from patients with APS induce the endothelial cell expression of Tissue Factor (TF) by a LRP6 signal transduction pathway involving lipid rafts. HUVEC were stimulated with affinity purified anti-beta 2-GPI antibodies. Both LRP6 and beta-catenin phosphorylation, as well as TF expression, were evaluated by western blot. Results demonstrated that triggering with affinity purified anti-beta 2-GPI antibodies induced LRP6 phosphorylation with consequent beta-catenin activation, leading to TF expression on the cell surface. Interestingly, the lipid rafts affecting agent methyl-beta-cyclodextrin as well as the LRP6 inhibitor Dickkopf 1 (DKK1) partially reduced the anti-beta 2-GPI antibodies effect, indicating that the anti-beta 2-GPI effects on TF expression may depend on a signalling transduction pathway involving both lipid rafts and LRP6. An interaction between beta 2-GPI, LRP6 and PAR-2 within these microdomains was demonstrated by gradient fractionation and coimmunoprecipitation experiments. Thus, anti-beta 2-GPI antibodies react with their target antigen likely associated to LRP6 and PAR-2 within plasma membrane lipid rafts of the endothelial cell. Anti-beta 2-GPI binding triggers beta-catenin phosphorylation, leading to a procoagulant phenotype characterized by TF expression. These findings deal with a novel signal transduction pathway which provides new insight in the APS pathogenesis, improving the knowledge of valuable therapeutic target(s).
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