title: Factor VII-activating protease promotes the proteolysis and inhibition of tissue factor pathway inhibitor.
abstract: OBJECTIVE
  Factor VII-activating protease (FSAP) activates both factor VII and pro-urokinase and inhibits platelet-derived growth factor-BB, thus regulating hemostasis- 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 of 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
  Using screening procedures to determine the influence of FSAP on various hemostasis-related processes on endothelial cells, we discovered that FSAP inhibited tissue factor pathway inhibitor (TFPI), a major anticoagulant 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 hemostasis and proliferative remodeling events in the vasculature.
authors: Institute for Biochemistry, Justus-Liebig-University, Friedrichstrasse 24, D-35392 Giessen, Germany. sandip.kanse@biochemie.med.uni-giessen.de
authors: Sandip M
authors: SM
authors: Kanse
authors: Paul J
authors: PJ
authors: Declerck
authors: Wolfram
authors: W
authors: Ruf
authors: George
authors: G
authors: Broze
authors: Michael
authors: M
authors: Etscheid
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D008074:Lipoproteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D012697:Serine Endopeptidases / Q000187:drug effects / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; C433550:HABP2 protein, human; D012697:Serine Endopeptidases