The functions of factor VII activating protease (FSAP) in the vascular system have been investigated. Marburg I (MI)-FSAP-polymorphism correlates with various vascular diseases and is characterized by a reduced proteolytic activity. Hence, the activity of FSAP appears to be of pivotal importance in vascular homeostasis. Further evidence for the contribution of FSAP to vascular pathophysiology was provided by the fact that FSAP-antigen and mRNA have been found within atherosclerotic plaques. FSAP circulates as an inactive zymogen in plasma and is activated by negatively charged polyanions. However, the precise mechanisms of FSAP-activation have not yet been elucidated. FSAP is known to inhibit platelet-derived growth factor (PDGF)-BB-mediated cell activation, whilst PDGF-BB is an important factor in the development of atherosclerosis and contributes to other fibrotic and cancer-related diseases.FSAP has been shown to be activated by heparin and RNA. Herein it has been demonstrated that polyphosphate, released by activated platelets, is a newly detected cofactor for FSAP. The high negative charge-to-size ratio and overall molecular size of polyanions qualify them as cofactors for FSAP. Furthermore, by using recombinant &
#916;EGF-3-FSAP, the importance of FSAP s EGF-3 domain in its interaction with polyanions could be confirmed. Heparin is released by mast cells, polyphosphate by platelets and RNA might be released from dying cells. Therefore, these cofactors can be present at sites of atherosclerosis and regulate FSAP function in these circumstances.FSAP is inhibited by serine protease inhibitors, such as protease nexin (PN)-1, plasminogen activator inhibitor (PAI)-1 and antithrombin III. If FSAP was complexed with either PN-1 or PAI-1 its internalization in a LDL receptor-related protein (LRP)-dependent mechanism by smooth muscle cells and fibroblasts could be shown. Hence, LRP accounts for the clearance of FSAP-inhibitor complexes. The functionality of LRP is crucial in the regulation of PDGF-BB signaling. However, the interaction of FSAP-inhibitor complexes with LRP had no impact on the LRP-mediated regulation of PDGF-BB signal-transduction. The inhibitory effect of FSAP on PDGF-BB-dependent cell activation occurs through specific cleavage of the PDGF-BB molecule. The cleavage-sites of FSAP in the PDGF-BB molecule have been identified. This revealed that FSAP-dependent cleavage had destroyed the receptor binding motif of PDGF-BB. Hence, the reduced proteolytic activity of MI-FSAP is the determinant for its correlation with vascular diseases, which has been demonstrated by its inability to inhibit PDGF-BB-dependent smooth muscle cell activation. With the herein presented results, new insights into the complex mechanisms that are involved in FSAP-regulation have been created. The improved description of these mechanisms may lead to novel therapeutic approaches in the treatment of fibro-proliferative, cancer-related and atherosclerotic diseases.
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