TY - JOUR
T1 - Two receptor systems are involved in the plasma clearance of tissue-type plasminogen activator (t-PA) in vivo
AU - Narita, M.
AU - Bu, G.
AU - Herz, J.
AU - Schwartz, A. L.
PY - 1995/8
Y1 - 1995/8
N2 - Tissue-type plasminogen activator (t-PA) is a serine protease, catalyzing the initial step in the fibrinolytic process. Intravenously administered t- PA is rapidly cleared from the circulation by the liver. Two distinct clearance mechanisms, which are mediated by the low density lipoprotein receptor-related protein (LRP) on liver parenchymal cells and by the mannose receptor on liver endothelial cells, have been described. Using competitors and inhibitors of the receptors, we investigated the role of LRP and carbohydrate receptors in t-PA clearance in vivo. To inhibit LRP, the 39-kD protein, which is a potent inhibitor of LRP activity, was overexpressed in the liver of mice using an adenoviral gene transfer technique. Expression of the 39-kD protein resulted in a sustained plasma concentration and an increase in the plasma half-life of 125I-t-PA from less than 1 min to 4-5 min. Blockade of the mannose receptor by intravenous administration of ovalbumin also prolonged the plasma half-life of 125I-t-PA to 3-4 min. The same degree of inhibition of t-PA clearance was also observed after administration of an inhibitor of the fucose receptor, fucosyl-BSA. However, under the conditions established for the complete blockade of the mannose receptor, no additional inhibition of t-PA clearance was observed using fucosyl-BSA, suggesting little or no role for the fucose receptor in the clearance of t-PA. Furthermore, a dramatic increase of the plasma half-life of 125I-t-PA (>> 20 min) was observed in mice overexpressing 39-kD protein and administered ovalbumin±fucosyl-BSA. Our results clearly demonstrate that two independent receptor systems, LRP and the mannose receptor, are involved in the hepatic clearance of t-PA.
AB - Tissue-type plasminogen activator (t-PA) is a serine protease, catalyzing the initial step in the fibrinolytic process. Intravenously administered t- PA is rapidly cleared from the circulation by the liver. Two distinct clearance mechanisms, which are mediated by the low density lipoprotein receptor-related protein (LRP) on liver parenchymal cells and by the mannose receptor on liver endothelial cells, have been described. Using competitors and inhibitors of the receptors, we investigated the role of LRP and carbohydrate receptors in t-PA clearance in vivo. To inhibit LRP, the 39-kD protein, which is a potent inhibitor of LRP activity, was overexpressed in the liver of mice using an adenoviral gene transfer technique. Expression of the 39-kD protein resulted in a sustained plasma concentration and an increase in the plasma half-life of 125I-t-PA from less than 1 min to 4-5 min. Blockade of the mannose receptor by intravenous administration of ovalbumin also prolonged the plasma half-life of 125I-t-PA to 3-4 min. The same degree of inhibition of t-PA clearance was also observed after administration of an inhibitor of the fucose receptor, fucosyl-BSA. However, under the conditions established for the complete blockade of the mannose receptor, no additional inhibition of t-PA clearance was observed using fucosyl-BSA, suggesting little or no role for the fucose receptor in the clearance of t-PA. Furthermore, a dramatic increase of the plasma half-life of 125I-t-PA (>> 20 min) was observed in mice overexpressing 39-kD protein and administered ovalbumin±fucosyl-BSA. Our results clearly demonstrate that two independent receptor systems, LRP and the mannose receptor, are involved in the hepatic clearance of t-PA.
KW - 39-kD protein
KW - adenovirus
KW - low density lipoprotein receptor-related protein
KW - mannose receptor
KW - tissue-type plasminogen activator
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U2 - 10.1172/JCI118105
DO - 10.1172/JCI118105
M3 - Article
C2 - 7635954
AN - SCOPUS:0029084057
SN - 0021-9738
VL - 96
SP - 1164
EP - 1168
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -