FXa-induced responses in vascular wall cells are PAR-mediated and inhibited by ZK-807834.

Abstract

During thrombosis, vascular wall cells are exposed to clotting factors, including the procoagulant proteases thrombin and factor Xa (FXa), both known to induce cell signaling. FXa shows dose-dependent induction of intracellular Ca(2+) transients in vascular wall cells that is active-site-dependent, Gla-domain-independent, and enhanced by FXa assembly into the prothrombinase complex. FXa signaling is independent of prothrombin activation as shown by the lack of inhibition by argatroban, hirudin and the sulfated C-terminal peptide of hirudin (Hir(54-65)(SO3(-))). This peptide binds to both proexosite I in prothrombin and exosite I in thrombin. In contrast, signaling is completely blocked by the FXa inhibitor ZK-807834 (CI-1031). No inhibition is observed by peptides which block interaction of FXa with effector cell protease 1 receptor (EPR-1), indicating that this receptor does not mediate signaling in the cells assayed. Receptor desensitization studies with thrombin or peptide agonists (PAR-1 or PAR-2) and experiments with PAR-1-blocking antibodies indicate that signaling by FXa is mediated by both PAR-1 and PAR-2. Potential pathophysiological responses to FXa include increased cell proliferation, increased production of the proinflammatory cytokine IL-6 and increased production of prothrombotic tissue factor. These cellular responses, which may complicate vascular disease, are inhibited by ZK-807834.

• Authors: K McLean, S Schirm, A Johns, J Morser, D R Light
• Journal: Thrombosis research (Thromb Res) Vol. 103 Issue 4 Pg. 281-97 (Aug 15 2001) ISSN: 0049-3848 [Print] United States
• PMID: 11562339 (Publication Type: Journal Article)

Chemical References

• Amidines
• BIRC5 protein, human
• Factor Xa Inhibitors
• Inhibitor of Apoptosis Proteins
• Pyridines
• Receptor, PAR-1
• Receptor, PAR-2
• Receptors, Cell Surface
• Receptors, Thrombin
• Serine Proteinase Inhibitors
• Survivin
• prothrombinase complex
• Fidexaban
• Factor V
• Thrombin
• Factor Xa

Topics

• Amidines (pharmacology)
• Calcium Signaling (drug effects)
• Cells, Cultured
• Endothelium, Vascular (cytology, drug effects)
• Factor V (pharmacology)
• Factor Xa (pharmacology)
• Factor Xa Inhibitors
• Humans
• Inhibitor of Apoptosis Proteins
• Pyridines (pharmacology)
• Receptor, PAR-1
• Receptor, PAR-2
• Receptors, Cell Surface
• Receptors, Thrombin (physiology)
• Serine Proteinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Survivin
• Thrombin (pharmacology)