The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation.
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.
Sedding
Daniel
D
Institute for Biochemistry, Justus-Liebig-University, 35392 Giessen, Germany.
Daniel
Jan-Marcus
JM
Muhl
Lars
L
Hersemeyer
Karin
K
Brunsch
Hannes
H
Kemkes-Matthes
Bettina
B
Braun-Dullaeus
Ruediger C
RC
Tillmanns
Harald
H
Weimer
Thomas
T
Preissner
Klaus T
KT
Kanse
Sandip M
SM
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
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