Inhibition of PDGF-BB by factor VII activating protease (FSAP) is neutralized by protease nexin-1, and the FSAP-inhibitor complexes are internalized via LRP - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biochemical Journal Année : 2007

Inhibition of PDGF-BB by factor VII activating protease (FSAP) is neutralized by protease nexin-1, and the FSAP-inhibitor complexes are internalized via LRP

Lars Muhl
  • Fonction : Auteur
Anders Nykjaer
  • Fonction : Auteur
Malgorzata Wygrecka
Denis Monard
  • Fonction : Auteur
Klaus T. Preissner
  • Fonction : Auteur

Résumé

Factor VII activating protease (FSAP) can inhibit neointima formation and vascular smooth muscle (VSMC) proliferation by cleavage of platelet derived growth factor-BB (PDGF-BB). Negatively charged polyanions lead to autoactivation of the FSAP but no information is available concerning the potential regulation of FSAP activity and its metabolism in the vessel wall. We now demonstrate that the enzymatic activity of FSAP can be inhibited by the serine protease inhibitor (SERPIN), protease nexin-1 (PN-1), that is found in the vasculature. This leads to the loss of the inhibitory effect of FSAP on PDGF-BB-mediated DNA synthesis and MAPK phosphorylation in VSMC. The FSAP-PN-1 complexes bind to the low density lipoprotein receptor related protein (LRP) and are subsequently internalized. This binding is inhibited by receptor associated protein (RAP) an antagonist of LRP as well as heparin. While PDGFβR is internalized by an LRP-dependent mechanism after stimulation of cells by PDGF-BB, the FSAP-PN-1 complexes neither influenced PDGF-BB-mediated phosphorylation of PDGFβR nor its internalization via LRP. Hence, PN-1 inhibits the enzymatic activity of FSAP and neutralizes its effect on PDGF-BB-mediated VSMC proliferation. The FSAP-inhibitor complexes are internalized via LRP without influencing the PDGF-BB signal transduction pathway.

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Dates et versions

hal-00478689 , version 1 (30-04-2010)

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Lars Muhl, Anders Nykjaer, Malgorzata Wygrecka, Denis Monard, Klaus T. Preissner, et al.. Inhibition of PDGF-BB by factor VII activating protease (FSAP) is neutralized by protease nexin-1, and the FSAP-inhibitor complexes are internalized via LRP. Biochemical Journal, 2007, 404 (2), pp.191-196. ⟨10.1042/BJ20061630⟩. ⟨hal-00478689⟩

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