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.
