Factor seven activating protease (FSAP); a key regulator of pericellular proteolysis
Abstract number: AS-TH-058
Daniel1 J., Uslu1 O., Hersemeyer1 K., Rannou1 O., Muhl1 L., Preissner1 K.T., Sedding2 D., Kanse1 S.M.
11Institute for Biochemistry 22Internal Medicine, Justus Liebig University, Giessen, Germany
How-to-cite Daniel J, Uslu O, Hersemeyer K, Rannou O, Muhl L, Preissner KT, Sedding D, Kanse SM. Factor seven activating protease (FSAP); a key regulator of pericellular proteolysis. Journal of Thrombosis and Haemostasis 2009; Volume 7, Supplement 2: Abstract AS-TH-058
Introduction: Factor VII activating protease (FSAP) can specifically activate pro-urokinase (pro-uPA) which in turn leads to an increased activation of plasminogen as well as matrix metalloproteases (MMPs), thereby contributing to pericellular proteolysis. We have investigated the influence of FSAP on the pericellular proteolysis system in the vasculature in vitro and in vivo.
Methods: The expression of uPA, tPA, MMP-2 and -9 (gelatinases) in endothelial cells (EC) and vascular smooth muscle cells (VSMC) was investigated in vitro under the influence of FSAP. We determined the (i) proteolytic activity by zymography and FRET peptide substrates, (ii) protein levels by Western blotting and (iii) mRNA levels by RT-PCR. The influence of FSAP on plasminogen activators as well as MMPs was also investigated in the vascular injury-induced neointima formation model using in situ zymography.
Results: FSAP activates pro-uPA to uPA but, over time, decreases the activity of uPA in EC and VSMC in a dose- and time-dependent manner. Protein levels of uPA were reduced and the enzymatic activity of FSAP was necessary for this effect. There was no influence on the levels of tissue plasminogen activator (tPA) or plasminogen activator inhibitor-1 (PAI-1). In contrast, an increase in the activity of gelatinases (MMP-2 and -9) was observed by zymography, but no changes in the levels of individual MMP proteins were noted. Pro-MMP-2 activation was much more prominent than pro-MMP-9 activation and this effect was mediated by FSAP through a non-proteolytic mechanism. There was no regulation of the levels of mRNA for uPA, tPA, MMP-2 and -9 as well as tissue inhibitors of matrix metalloproteinases (TIMPs). In the mouse vascular injury model FSAP application reduced uPA activity and increased gelatinase activity in the vessel wall in a similar manner as on cells in vitro. Conclusions: Although FSAP activates pro-uPA, it can also, proteolytically, inactivate uPA but not tPA. On the other hand, MMP-2 and -9 activity was increased by FSAP. These effects of FSAP alter the pericellular proteolysis balance in the vessel wall and can contribute to vascular remodelling processes.
Disclosure of interest: None.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
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