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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Becaplermin
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Catalysis
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Cell Proliferation / drug effects
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Coronary Restenosis / genetics*
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Coronary Restenosis / prevention & control
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression
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Heparin / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / pharmacology
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism
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Phosphorylation
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Platelet-Derived Growth Factor / metabolism
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Platelet-Derived Growth Factor / pharmacology
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Polymorphism, Genetic*
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Protein Binding
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Proto-Oncogene Proteins c-sis
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Serine Endopeptidases / genetics*
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Serine Endopeptidases / metabolism
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Serine Endopeptidases / pharmacology
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Serine Proteinase Inhibitors / pharmacology
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Tunica Intima / drug effects
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Tunica Intima / metabolism*
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Tunica Intima / pathology
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Urokinase-Type Plasminogen Activator / metabolism
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von Willebrand Factor / metabolism
Substances
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Actins
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Amino Acid Chloromethyl Ketones
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Intercellular Signaling Peptides and Proteins
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Serine Proteinase Inhibitors
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von Willebrand Factor
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Becaplermin
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Heparin
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Extracellular Signal-Regulated MAP Kinases
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HABP2 protein, human
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Serine Endopeptidases
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Urokinase-Type Plasminogen Activator
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phenylalanyl-prolyl-arginine-chloromethyl ketone