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Title: Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1
Authors: Van De Craen, Britt
Scroyen, Ilse
Vranckx, Christine
Compernolle, Griet
Lijnen, Roger
Declerck, Paul
Gils, Ann # ×
Issue Date: Apr-2012
Publisher: Pergamon Press
Series Title: Thrombosis Research vol:129 issue:4 pages:e126-e133
Abstract: Plasminogen activator inhibitor-1 (PAI-1) regulates the activity of t-PA and u-PA and is an important inhibitor of the plasminogen activator system. Elevated PAI-1 levels have been implicated in the pathogenesis of several diseases. Prior to the evaluation of PAI-1 inhibitors in humans, there is a strong need to study the effect of PAI-1 inhibition in mouse models. In the current study, four monoclonal antibodies previously reported to inhibit recombinant PAI-1 in vitro, were evaluated in an LPS-induced endotoxemia model in mice. Both MA-33H1F7 and MA-MP2D2 exerted a strong PAI-1 inhibitory effect, whereas for MA-H4B3 and MA-124K1 no reduced PAI-1 activity was observed in vivo. Importantly, the lack of PAI-1 inhibition observed for MA-124K1 and MA-H4B3 in vivo corresponded with the absence of inhibition toward glycosylated mouse PAI-1 in vitro. Three potential N-glycosylation sites were predicted for mouse PAI-1 (i.e. N209, N265 and N329). Electrophoretic mobility analysis of glycosylation knock-out mutants before and after deglycosylation indicates the presence of glycan chains at position N265. These data demonstrate that an inhibitory effect toward glycosylated PAI-1 is a prerequisite for efficient PAI-1 inhibition in mice. Our data also suggest that PAI-1 inhibitors for use in humans must preferably be screened on glycosylated PAI-1 and not on recombinant non-glycosylated PAI-1.
URI: 
ISSN: 0049-3848
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Laboratory for Pharmaceutical Biology (-)
× corresponding author
# (joint) last author

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