title: The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation.
abstract: The G534E polymorphism (Marburg I [MI]) of factor VII-activating protease (FSAP) is associated with carotid stenosis and cardiovascular disease. We have previously demonstrated that FSAP is present in atherosclerotic plaques and it is a potent inhibitor of vascular smooth muscle proliferation and migration in vitro. The effect of wild-type (WT)- and MI-FSAP on neointima formation in the mouse femoral artery after wire-induced injury was investigated. Local application of WT-FSAP led to a 70% reduction in the neointima formation, and this effect was dependent on the protease activity of FSAP. MI-FSAP did not inhibit neointima formation in vivo. This is due to a reduced proteolytic activity of MI-FSAP, compared to WT-FSAP, toward platelet-derived growth factor BB, a key mediator of neointima development. The inability of MI-FSAP to inhibit vascular smooth muscle accumulation explains the observed linkage between the MI-polymorphism and increased cardiovascular risk. Hence, FSAP has a protective function in the vasculature, and analysis of MI polymorphism is likely to be clinically relevant in restenosis.
authors.affiliation: Institute for Biochemistry, Justus-Liebig-University, 35392 Giessen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sedding
authors.forename: Jan-Marcus
authors.initials: JM
authors.lastname: Daniel
authors.forename: Lars
authors.initials: L
authors.lastname: Muhl
authors.forename: Karin
authors.initials: K
authors.lastname: Hersemeyer
authors.forename: Hannes
authors.initials: H
authors.lastname: Brunsch
authors.forename: Bettina
authors.initials: B
authors.lastname: Kemkes-Matthes
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimer
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Sandip M
authors.initials: SM
authors.lastname: Kanse
mesh_terms: D000199:Actins / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D002384:Catalysis; D049109:Cell Proliferation / Q000187:drug effects; D023903:Coronary Restenosis / Q000235:genetics* / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006493:Heparin / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000199:Actins; D000590:Amino Acid Chloromethyl Ketones; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D015842:Serine Proteinase Inhibitors; D014841:von Willebrand Factor; D000077214:Becaplermin; D006493:Heparin; D048049:Extracellular Signal-Regulated MAP Kinases; C433550:HABP2 protein, human; D012697:Serine Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone