Factor Xa induces tissue factor expression in endothelial cells by P44/42 MAPK and NF-κB-dependent pathways

Area of Science:

• Vascular Biology
• Coagulation Cascade
• Inflammation Signaling

Background:

• Tissue factor (TF) initiates coagulation and plays a role in inflammation.
• Factor Xa (FXa), a key enzyme in coagulation, has non-hemostatic functions, including inflammatory responses in endothelial cells.
• Understanding FXa's role in inflammation is critical for procedures involving inflammatory triggers.

Purpose of the Study:

• To investigate if FXa up-regulates TF on vascular endothelial cells.
• To determine the involvement of mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways in FXa-induced TF expression.

Main Methods:

• Cultured human umbilical vein endothelial cells (HUVECs) were incubated with FXa.
• TF protein expression and activity were measured.
• Specific inhibitors for serine proteases (antithrombin, hirudin), MAPK pathway (PD98059), NF-κB pathway (Bay 11-7802), and PI3 kinase (LY294002) were used to elucidate signaling mechanisms.

Main Results:

• FXa dose-dependently increased TF protein expression and activity in HUVECs.
• FXa induced rapid activation of P44/42 MAPK and NF-κB signaling.
• Inhibition of MAPK and NF-κB pathways significantly reduced FXa-induced TF expression, while PI3 kinase inhibition had no effect.
• FXa-induced TF upregulation was independent of the thrombin-PAR1 pathway.

Conclusions:

• FXa up-regulates TF expression and activity in HUVECs through MAPK and NF-κB dependent pathways.
• The observed FXa-induced TF upregulation is independent of the thrombin-PAR1 pathway.
• FXa may represent a feed-forward mechanism for TF activation, contributing to procoagulant states and inflammation, particularly relevant in cardiac surgery.