The in vivo effects of the factor VII-activating protease (FSAP) on neointima formation
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Factor VII activating protease (FSAP), a novel plasma protease, can activate both Factor VII independently of tissue factor and pro-urokinase plasminogen activator (uPA). The FSAP gene has been linked to vascular diseases in humans, since the Marburg I (MI, G534E) polymorphism is a prominent risk factor for atherosclerosis and stroke. Furthermore, enhanced FSAP staining was detected in instable atherosclerotic plaques. In contrast to wild type (WT)-FSAP, MI-FSAP has lower enzymatic activity and does not inhibit proliferation of vascular smooth muscle cells (VSMC) due to specific cleavage of platelet-derived growth factor (PDGF)-BB in vitro.In this study, the effect of WT- and MI-FSAP on neointima formation was investigated in a mouse model of wire induced injury of the femoral artery. WT-FSAP was locally applied to the denuded artery in different concentrations and was then compared to MI-FSAP, as well as the active site-inhibited Phe-Pro-Arg-chloromethylketone (PPACK)-FSAP, and a buffer control. WT-FSAP attenuated neointima formation in a dose dependent manner and inhibited proliferation of VSMC, as determined by expression of the proliferating cell nuclear antigen. Since MI-FSAP and PPACK-FSAP did not attenuate neointima formation, the effects of FSAP were mainly due to its proteolytic activity. Following in situ zymography, application of WT-FSAP changed the proteolysis balance in the vessel wall by reducing endogenous plasmin activity. Corresponding to this regulation, the neointima in uPA-/- mice was mainly acellular and nearly completely lacked VSMC. Furthermore, FSAP application did not influence the trans-differentiation of bone marrow-derived progenitor cells into VSMC. Indeed, these cells were predominantly identified as macrophages and could no longer be detected in the vascular wall, when the inflammatory response to the vascular injury had calmed down.The inability of MI-FSAP to inhibit VSMC proliferation in vivo explains the observed linkage between the MI-polymorphism and increased cardiovascular risk. Moreover, FSAP is a prominent regulator of the proteolysis balance at sites of tissue remodelling and could thus account for its association with plaque stability. Hence, FSAP is an important regulator of vascular remodelling with high clinical relevance.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Arterioscler Thromb Vasc Biol. 2010, 30(10):1890-6, J Exp Med. 2006, 203(13):2801-7