Download PDF
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

Authors

  • 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
Further Information

Publication History

Received 30 December 1994

Accepted after revision 02 August 1995

Publication Date:
10 July 2018 (online)

 PDF Download  Permissions and Reprints

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.

 

  • References

  • 1 Bu G, Warshawsky I, Schwartz AL. Cellular receptors for the plasminogen activators. Blood 1994; 83: 3427-3436
    Search in Google Scholar
  • 2 Otter M, Kuiper J, Berkel ThJ C van, Rijken DC. Mechanisms of tissue- type plasminogen activator clearance by the liver. Ann NY Acad Sci 1992; 667: 431-442
    CrossrefSearch in Google Scholar
  • 3 Krause J. Catabolism of tissue-type plasminogen activator, its variants, mutants and hybrids. Fibrinolysis 1988; 2: 133-142
    Search in Google Scholar
  • 4 Kuiper J, Otter M, Rijken DC, van Berkel ThJC. Characterization of the interaction in vivo of tissue-type plasminogen activator with liver cells. J Biol Chem 1988; 263: 18220-18224
    Search in Google Scholar
  • 5 Einarsson M, Smedsrød B, Pertoft H. Uptake and degradation of tissue type plasminogen activator in rat liver. Thromb Haemost 1988; 59: 474-479
    Thieme ConnectSearch in Google Scholar
  • 6 Otter M, Zockova P, Kuiper J, van Berkel ThJC, Barrett-Bergshoef MM, Rijken DC. Isolation and characterization of the mannose receptor from human liver potentially involved in the plasma clearance of tissue-type plasminogen activator. Hepatology 1992; 16: 54-59
    CrossrefPubMedSearch in Google Scholar
  • 7 Otter M, Barrett-Bergshoef MM, Rijken DC. Binding of tissue-type plasminogen activator by the mannose receptor. J Biol Chem 1991; 266: 13931-13935
    Search in Google Scholar
  • 8 Morton PA, Owensby DA, Sobel BE, Schwartz AL. Catabolism of tissue- type plasminogen activator by human hepatoma cell line Hep G2. Modulation by plasminogen activator inhibitor type I J Biol Chem 1989; 264: 7228-7235
    Search in Google Scholar
  • 9 Owensby DA, Morton PA, Schwartz AL. Interactions between tissue-type plasminogen activator and extracellular matrix-associated plasminogen activator inhibitor type 1 in the human hepatoma cell line Hep G2. J Biol Chem 1989; 264: 18180-18187
    Search in Google Scholar
  • 10 Bu G, Maksymovitch EA, Schwartz AL. Receptor mediated endocytosis of tissue-type plasminogen activator by LRP on human hepatoma Hep G2 cells. J Biol Chem 1993; 268: 13002-13008
    Search in Google Scholar
  • 11 Bu G, Williams S, Strickland DK, Schwartz AL. Low density lipoprotein receptor related protein/α2-macroglobulin receptor is a hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci USA 1992; 89: 7427-7431
    CrossrefSearch in Google Scholar
  • 12 Orth K, Madison EL, Gething M, Sambrook JF, Herz J. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen activator inhibitor type 1 are internalized by means of the low-density lipoprotein receptor related protein/α2-macroglobulin receptor. Proc Natl Acad Sci USA 1992; 89: 7422-7426
    CrossrefSearch in Google Scholar
  • 13 Orth K, Willnow T, Herz J, Gething MJ, Sambrook JF. Low-density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator. J Biol Chem 1994; 269: 21117-21122
    Search in Google Scholar
  • 14 Wing LR, Combe CJ, Bennett B, Booth NA. A receptor on primary human hepatocytes for tissue-type plasminogen activator-plasminogen activator inhibitor type-I and plasmin-α2-antiplasmin complexes. Fibrinolysis 1992; 6: 2
    Search in Google Scholar
  • 15 Combe CJ, Booth NA. Plasmin-α2-macroglobulin complex is not a ligand for the receptor on human hepatocytes for plasmin-α2-antiplasmin complex and tissue-type plasminogen activator in complex with its inhibitor PAI-1. Thromb Haemost 1993; 69: 543
    Thieme ConnectSearch in Google Scholar
  • 16 Haijar KA, Reynolds CM. α-fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells. J Clin Invest 1994; 93: 703-710
    CrossrefSearch in Google Scholar
  • 17 Camani C, Bachman F, Kruithof EKO. The role of plasminogen activator inhibitor type-1 in the clearance of tissue-type plasminogen activator by rat hepatoma cells. J Biol Chem 1994; 269: 5770-5775
    PubMedSearch in Google Scholar
  • 18 Smedsrød B, Einarsson M, Pertoft H. Tissue-type plasminogen activator is endocytosed by mannose and galactose receptors on rat liver cells. Thromb Haemost 1988; 59: 480-484
    Thieme ConnectSearch in Google Scholar
  • 19 Otter M, Kuiper J, Bos R, van Berkel ThJC, Rijken DC. Characterization of the interaction both in vivo and in vitro of tissue-type plasminogen activator with rat liver cells. Biochem J 1992; 284: 545-550
    CrossrefSearch in Google Scholar
  • 20 Otter M, van Berkel ThJC, Rijken DC. Binding and degradation of tissue- type plasminogen activator by the human hepatoma cell line HepG2. Thromb Haemost 1989; 62: 667-672
    Thieme ConnectSearch in Google Scholar
  • 21 Warshawsky I, Bu G, Schwartz AL. 39 kD protein inhibits tissue-type plasminogen activator clearance in vivo. J Clin Invest 1993; 92: 937-944
    CrossrefSearch in Google Scholar
  • 22 Smedsrød B, Einarsson M. Clearance of tissue-type plasminogen activator by mannose and galactose receptors in the liver. Thromb Haemost 1990; 63: 60-66
    Thieme ConnectSearch in Google Scholar
  • 23 Bakhit C, Lewis D, Billings R, Malfroy B. Cellular catabolism of recombinant tissue-type plasminogen activator. J Biol Chem 1987; 262: 8716-8720
    Search in Google Scholar
  • 24 Ehrlich HJ, Klein Gebbink R, Keijer L, Linders M, Preissner KT, Pannekoek H. Alteration of serpin specificity by a protein cofactor. J Biol Chem 1990; 265: 13029-13035
    Search in Google Scholar
  • 25 Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS. 39-kDa protein modulates binding of ligands to low-density lipoprotein receptor-related protein/α2-macroglobulin receptor. J Biol Chem 1991; 266: 21232-21238
    Search in Google Scholar
  • 26 Voorschuur AH, Kuiper J, Neelissen JAM, Boers W, van Berkel ThJC. Different zonal distribution of the asialoglycoprotein receptor, the α2-macroglobulin receptor/low-density lipoprotein receptor-related protein and the lipoprotein-remnant receptor of rat liver parenchymal cells. Biochem J 1994; 303: 809-816
    CrossrefSearch in Google Scholar
  • 27 Van Berkel ThJC, de Rijke YB, Kruyt JK. Different fate in vivo of oxidatively modified-LDL and acetylated-LDL in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells J Biol Chem 1991; 266: 2282-2289
    Search in Google Scholar
  • 28 Kuiper J, Rijken DC, de Munk GA W, van Berkel ThJC. In vivo and in vitro interaction of high- and low-molecular weight single chain urokinase-type plasminogen activator with rat liver cells. J Biol Chem 1992; 267: 1589-1595
    Search in Google Scholar
  • 29 Seglen PO. Isolation of liver cells. Methods Cell Biol 1976; 13: 29-83
    Search in Google Scholar
  • 30 Casteleyn E, van Rooij HC J, van Berkel Th J C, Koster JF. Mechanism of glucagon stimulation of fructose- 1,6-bisphosphate in rat hepatocytes. FEBS Lett 1986; 201: 193-197
    CrossrefSearch in Google Scholar
  • 31 Wing LR, Hawksworth GM, Bennet B, Booth NA. Clearance of tissue-type plasminogen activator, PAI-1 and tissue-type plasminogen activator PAI-1 complex in an isolated perfused rat liver system. J Lab Clin Med 1991; 117: 109-114
    Search in Google Scholar
  • 32 Mokuno H, Brady S, Kotice L, Herz J, Havel RJ. Effect of the 39-kDa receptor associated protein on the hepatic uptake and endocytosis of chylomicron remnants and low-density lipoproteins in the rat. J Biol Chem 1994; 269: 13238-13243
    Search in Google Scholar
  • 33 Moestrup SK, Holtet TL, Etzerodt M, Thøgersen HC, Nykjaer A, Andreasen PA, Rasmussen HR, Sottrup-Jensen L, Gliemann J. α2-Macroglobulin-proteinase complexes, plasminogen activator inhibitor type-1-plasminogen activator complexes, and receptor-associated protein bind to a region of the α2-macroglobulin receptor containing a cluster of eight complement-type repeats. J Biol Chem 1993; 268: 13691-13696
    Search in Google Scholar
  • 34 Van Dijk MC M, Kruijt JK, Boers W, Linthorst C, Van Berkel ThJC. Distinct properties of the recognition sites for (3-very low density lipoprotein (remnant receptor) and α2-macroglobulin (low-density lipoprotein receptor- related protein) on rat parenchymal cells. J Biol Chem 1992; 267: 17732-17737
    Search in Google Scholar
  • 35 Williams SE, Ashcom JD, Argraves WS, Strickland DK. A novel mechanism for controlling the activity of α2-macroglobulin receptor/low density lipoprotein receptor-related protein. J Biol Chem 1992; 267: 9035-9040
    CrossrefPubMedSearch in Google Scholar
  • 36 Moestrup SK, Gliemann J. Analysis of ligand recognition by the purified a2-macroglobulin receptor (low-density lipoprotein receptor-related protein). J Biol Chem 1991; 266: 14011-14017
    Search in Google Scholar
  • 37 Chan AL, Morris HR, Panico M, Etienne AT, Rogers ME, Gaffney P, Creighton-Kempsford L, Dell A. A novel sialylated N-acetylgalactos-amine-containing oligosaccharide is the major complex-type structure present in Bowes melanoma tissue plasminogen activator. Glycobiol 1991; 1: 173-185
    CrossrefSearch in Google Scholar