2 RECEPTOR SYSTEMS ARE INVOLVED IN THE PLASMA-CLEARANCE OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR (T-PA) IN-VIVO

Tissue-type plasminogen activator (t-PA) is a serine protease, catalyz ing the initial step in the fibrinolytic process, Intravenously admini stered t-PA is rapidly cleared from the circulation by the liver, Two distinct clearance mechanisms, which are mediated by the low density l ipoprotein receptor-related protein (LRP) on liver parenchymal cells a nd by the mannose receptor on liver endothelial cells, have been descr ibed, Using competitors and inhibitors of the receptors, we investigat ed the role of LRP and carbohydrate receptors in t-PA clearance in viv o, To inhibit LRP, the 39-kD protein, which is a potent inhibitor of L RP activity, was overexpressed in the liver of mice using an adenovira l gene transfer technique, Expression of the 39-KD protein resulted in a sustained plasma concentration and an increase in the plasma half-l ife of I-125-t-PA from less than I min to 4-5 min, Blockade of the man nose receptor by intravenous administration of ovalbumin also prolonge d the plasma half-life of I-125-t-PA to 3-4 min, The same degree of in hibition of t-PA clearance was also observed after administration of a n inhibitor of the fucose receptor, fucosyl-BSA, However, under the co nditions established for the complete blockade of the mannose receptor , no additional inhibition of t-PA clearance was observed using fucosy l-BSA, suggesting little or no role for the fucose receptor in the cle arance of t-PA, Furthermore, a dramatic increase of the plasma half-li fe of I-125-t-PA (much greater than 20 min) was observed in mice overe xpressing 39-kD protein and administered ovalbumin +/- fucosyl-BSA. Ou r results clearly demonstrate that two independent receptor systems, L RP and the mannose receptor, are involved in the hepatic clearance of t-PA.