Simvastatin competitively inhibits cellular signaling of lipid-binding antiphospholipid antibodies
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Abstract
Background
Antiphospholipid antibodies (aPLs) 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.
Objectives
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.
Methods
Cultured monocytes were treated with human monoclonal lipid-binding aPLs or total immunoglobulin G fractions positive for cardiolipin antibodies with or without statins. Expression of TF and tumor necrosis factor α (TNFα) messenger RNA was measured by real-time quantitative polymerase chain reaction. 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.
Results
Simvastatin completely inhibited the induction of TNFα and TF messenger RNA by human lipid-binding aPLs. Simvastatin also prevented TF activation by aPL on the cell surface. These effects were not mediated by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition, but simvastatin and other statins prevented lipid-binding aPLs from binding to their cell-surface target, ie, 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, aPLs could not induce any downstream cellular effects.
Conclusion
Our data show that statins prevent monocyte activation and TF-triggered coagulation by interfering with binding of lipid-binding aPLs 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.
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Journal of thrombosis and haemostasis, 23, 12, Elsevier, Amsterdam, 2025, https://doi.org/10.1016/j.jtha.2025.08.027