Role of the low density lipoprotein receptorrelated protein (lrp) in the clearance and liver uptake of recombinant single chain urokinase-type plasminogen activator (rscu-pa) in rats
article
Urokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, E.coli produced rscu-PA is recognized by LRP on parenchyma! liver cells. In this study we investigated the role of LRP in the liver uptake and plasma clearance of rscu-PA. A preinjection of the LRP inhibitor GSTRAP reduced the maximal liver uptake of IMl-rscu-PA from 50 to 30 % of the injected dose and decreased the clearance from 2.37 ml/min to 1.58 ml/min. Parenchymal, Kupffer and endothelial cells were responsible for 40, 50 and 10 % of the liver uptake, respectively. The 40 % reduction in liver uptake of rscu-PA by preinjection of GST-RAP was caused by a 91 % and 62 % reduction in the uptake by the parenchymal and Kupffer cells, respectively. Deletion of residue 11 -135 from rscu-PA (=delta125-rscu-PA) resulted in a 80 % reduction in liver uptake and a 2.4 times slower clearance (0.97 ml/min). The parenchymal, Kupffer and endothelial cells were responsible for the uptake of 60.2, 32.9 and 7.0 % of 125l-delta125-rscu-PA in the liver. Preinjection of GST-RAP completely reduced the liver uptake and reduced the clearance to 0.79 ml/min. Treatment of Kupffer cells with pl-PLC reduced the binding of rscu-PA by 40 %, indicating the involvement of u-PAR in the recognition of rscu-PA by the Kupffer cells. Our results demonstrate that in vivo LRP is responsible for the parenchymal liver cell mediated uptake of rscu-PA and for 60 % of the Kupffer cell interaction. It is also shown that u-PAR is involved in the Kupffer cell recognition of rscu-PA.
TNO Identifier
233627
ISSN
02689499
Source
Fibrinolysis, 10(SUPPL. 3), pp. 5.
Pages
5
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