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Thromb Haemost 1995; 74(05): 1298-1304
DOI: 10.1055/s-0038-1649930
Original Article
Fibrinolysis
Schattauer GmbH Stuttgart

Characterization of the Interaction of a Complex of Tissue-type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 with Rat Liver Cells

J Kuiper
1   The Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, University of Leiden, Leiden, The Netherlands
,
M Otter
2   The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
,
A H Voorschuur
1   The Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, University of Leiden, Leiden, The Netherlands
,
A J van Zonneveld
3   The Department of Biochemistry, Amsterdam Medical Center, Amsterdam, The Netherlands
,
D C Rijken
2   The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
,
Th J C van Berkel
1   The Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, University of Leiden, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 30 December 1994

Accepted after revision 02 August 1995

Publication Date:
10 July 2018 (online)

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Summary

The present study was undertaken in order to determine the recognition site for tissue-type plasminogen activator-plasminogen activator inhibitor type 1 [t-PA-PAI-1] complexes in rat liver in vivo and in vitro. After intravenous injection into rats t-PA-PAI-1 complexes were rapidly removed from the plasma and the liver took up 80% of the injected dose. Within the liver parenchymal and endothelial liver cells contributed mainly to the uptake of t-PA-PAI-1, and were responsible for 62% and 24% of the liver uptake, respectively. The interaction of t-PA- PAI-1 with isolated rat parenchymal liver cells was of high affinity (Kd 17 nM). A well-known antagonist of the α2-macroglobulin receptor (α2MR/low-density lipoprotein receptor-related protein (LRP), GST-39kDa protein (GST-39kDaP) efficiently inhibited the binding (IC50 0.7 nM) of t-PA-PAI-1 to rat parenchymal liver cells. The interaction of t-PA-PAI-1 with LRP on rat parenchymal liver cells was not Ca2+-dependent and is most probably mediated by a specific determinant on PAI-1, since an anti-PAI-1 monoclonal antibody inhibited the binding of t-PA-PAI-1, where as free t-PA did not. The binding of t-PA-PAI-1 to rat hepatocytes could not be inhibited by a complex of plasmin and α2-antiplasmin nor by various other ligands of LRP like β-VLDL and lactoferrin. Binding of t-PA-PAI-1 to rat parenchymal liver cells was followed by internalization and subsequent degradation in the lysosomal compartment.

It is concluded that parenchymal and endothelial liver cells mediate the removal of t-PA-PAI-1 complexes from the circulation. LRP on rat parenchymal liver cells is responsible for the uptake and degradation of t-PA-PAI-1 and may therefore be important for the regulation of the t-PA levels in the circulation.

 

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