PB0705 Pharmacological Inhibition of Coagulation Factor XI Reduces Thromboinflammation in a Nonhuman Primate Model of Early Atherosclerosis
Year: 2023
Type: conference-abstract
Abstract: Background: Proteolysis of vascular endothelial (VE)-cadherin is a biomarker for endothelial cell (EC) barrier disruption, with elevated levels of soluble VE (sVE)-cadherin associated with atherosclerosis and sepsis.Factor XI (FXI) plays a regulatory role in inflammation, and while a relationship between FXI activity and VE-cadherin expression levels has been observed, a mechanism by which FXI affects sVE-cadherin production is unknown.Aims: Activated FXI (FXIa) induces VE-cadherin proteolysis.Methods: Human umbilical vein ECs were stimulated with FXIa (30 and 5 nM) for six hours.Western blot analysis was used to study VE-cadherin proteolysis, disintegrin and metalloproteinase 10 (ADAM10) expression, FXIa-PAI-1 or -very low density lipoprotein receptor (VLDLR) interactions, and cell signaling events.SVE-cadherin in baboons challenged with heatinactivated Staphylococcus aureus was detected by ELISA.Results: FXIa induced expression of active ADAM10 on ECs, generated a VE-cadherin fragment and increased ECs permeability.This was reversed by the serine protease inhibitor, PPACK, and an ADAM10 inhibitor.Receptorassociated protein (RAP) inhibited FXIa-induced VE-cadherin proteolysis by preventing FXIa interaction with PAI-1 and VLDLR on ECs.FXIa-VLDLR interaction induced Dab1 and Src kinase phosphorylation.Furthermore, FXIa activated the VEGFR2-PLCgamma1-ERK1/2 signaling pathway, and ERK1/2 and Src kinase inhibition via LY3214996 and PP2, respectively, inhibited FXIa-induced VE-cadherin proteolysis.PLCgamma1 phosphorylation was also prevented with PP2.The VEGFR2 kinase inhibitor, SU1498, prevented the cleavage of VE-cadherin by FXIa; in contrast, a VEGF blocking antibody had no effect on FXIa-induced VE-cadherin cleavage.Finally, the inhibition of FXI activation in a baboon model of sepsis significantly decreased the levels of sVE-cadherin.Conclusion(s): FXIa induces VE-cadherin proteolysis via an interaction with PAI-1 and VLDLR, thus promoting Src kinase phosphorylation, VEGFR2-PLCgamma1-ERK1/2 signaling, and trafficking of active ADAM10 to EC surfaces.FXI may be a druggable target to protect EC barrier function in inflammatory diseases.
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,250
OpenAlex ID: W4388597544