Simvastatin competitively inhibits cellular signalling of lipid-binding antiphospholipid antibodies.

Background and purpose: Antiphospholipid antibodies (aPL) cause antiphospholipid syndrome (APS), a disease characterized by thrombotic events and/or pregnancy morbidity. Some clinical studies suggest that statins may beneficially affect the course of APS. In this study, we studied the effect of statins on aPL-induced monocyte activation, aPL-triggered tissue factor (TF) activation and the underlying cellular mechanisms.

Experimental approach: Cultured monocytes were treated with human monoclonal lipid-binding aPL or total IgG fractions positive for cardiolipin antibodies with or without statins. Expression of TF and TNFα mRNA was measured by real-time quantitative PCR. TF activity was determined using clotting assay. The effects of statins on the binding and internalization of aPL were determined by confocal microscopy and flow cytometry.

Key results: Simvastatin completely inhibited the induction of TNFα and TF mRNA by human lipid-binding aPL. Simvastatin also prevented TF activation by aPL on the cell surface. These effects were not mediated by HMGCoA-reductase inhibition, but simvastatin and other statins prevented lipid-binding aPL from binding to their cell surface target, i.e. lysobisphosphatidic acid (LBPA) presented by the endothelial protein C-receptor (EPCR) by displacement of LBPA. Competition experiments indicate that statins displace LBPA from the hydrophobic groove of EPCR. Consequently, aPL could not induce any downstream cellular effects.

Conclusion and implications: Our data show that statins prevent monocyte activation and TF-triggered coagulation by interfering with binding of lipid-binding aPL to the EPCR/LBPA complex on the cell surface of monocytes. These findings may help to understand the observed beneficial effects of statins in APS.