Factor VII–Activating Protease Promotes the Proteolysis and Inhibition of Tissue Factor Pathway Inhibitor

Abstract

Objectives Factor VII activating protease (FSAP) activates FVII as well as pro-urokinase and inhibits platelet-derived growth factor-BB, thus regulating haemostasis- and remodeling-associated processes in the vasculature. A genetic variant of FSAP (Marburg I polymorphism) results in low enzymatic activity and is associated with an enhanced risk for carotid stenosis and stroke. We postulate that there are additional substrates for FSAP that will help to explain its role in vascular biology and have searched for such a substrate. Results and Methods Using screening procedures to determine the influence of FSAP on various haemostasis-related processes on endothelial cells we discovered that FSAP inhibited tissue factor pathway inhibitor (TFPI), a major anti-coagulant secreted by these cells. Proteolytic degradation of TFPI by FSAP could also be demonstrated by Western blotting and the exact cleavage sites were determined by N-terminal sequencing. The Marburg I variant of FSAP had a diminished ability to inhibit TFPI. A monoclonal antibody to FSAP, that specifically inhibited FSAP binding to TFPI, reversed the inhibitory effect of FSAP on TFPI. Conclusions The identification of TFPI as a sensitive substrate for FSAP increases our understanding of its role in regulating haemostasis and proliferative remodeling events in the vasculature.

Role of glycine 221 in catalytic activity of hyaluronan-binding protein 2

“…In contrast, HABP2 does effectively activate single-chain urokinase-type plasminogen activator (scuPA), 2 suggesting a role in fibrinolysis (3)(4)(5). HABP2 has further been reported to cleave tissuefactor pathway inhibitor (6). Interestingly, HABP2/FSAP knockout mice display a mild bleeding phenotype, suggesting a role in hemostasis in relation to tissue-factor pathway inhibitor cleavage (7).…”

“…In view of the numerous substrates that have been proposed for HABP2 (3)(4)(5)(6)(7)10), it remains difficult to predict the phenotype associated with Gly-221 substitution. It remains plausible that HABP2 is a promiscuous enzyme that activates more substrates than scuPA alone and thus may have more roles than stimulation of fibrinolysis.…”

Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells

“…Other substrates for FSAP include; pro-uPA 51,52 , fibrinogen and fibronectin 52 , TFPI 53 , PDGF-BB 54 , bFGF/EGF 55 and kininogen 49,56 . In addition FSAP degrades histones from necrotic In patients with carotid stenosis, the presence of the MI-SNP was associated with a worse outcome 68 .…”

Circulating Factor VII Activating Protease (FSAP) Is Associated With Clinical Outcome in Acute Coronary Syndrome

“…10,11 FSAP also inactivates tissue factor pathway inhibitor (TFPI), which would also have a procoagulant effect on blood clotting. 12 More recently, various studies have supported the emerging role of FSAP in advanced atherosclerosis and cardiovascular diseases. [13][14][15][16][17] Next to hepatocytes, the major cellular source of intravascular FSAP is monocytes, the only blood cells capable of synthesizing FSAP in response to various inflammatory mediators such as cytokines and bacterial endotoxins.…”