Download PDF
Thromb Haemost 1995; 73(03): 458-465
DOI: 10.1055/s-0038-1653797
Original Articles
Fibrinolysis
Schattauer GmbH Stuttgart

Interaction of Lp(a) with Plasminogen Binding Sites on Cells

Lindsey A Miles
1   The Department of Vascular Biology and Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
,
Gunther M Fless
2   Department of Medicine, University of Chicago, Chicago, IL, USA
,
Angelo M Scanu
2   Department of Medicine, University of Chicago, Chicago, IL, USA
3   Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
,
Patricia Baynham
1   The Department of Vascular Biology and Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
,
Matthew T Sebald
1   The Department of Vascular Biology and Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
,
Pamela Skocir
4   Center for Thrombosis and Vascular Biology (FF20), Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
,
Linda K Curtiss
1   The Department of Vascular Biology and Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
,
Eugene G Levin
1   The Department of Vascular Biology and Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
,
Jane L Hoover-Plow
4   Center for Thrombosis and Vascular Biology (FF20), Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
,
Edward F Plow
4   Center for Thrombosis and Vascular Biology (FF20), Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
› Author Affiliations
Further Information

Publication History

Received14 June 1994

Accepted after resubmission 21 November 1994

Publication Date:
09 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Lp(a) competes with plasminogen for binding to cells but it is not known whether this competition is due to the ability of Lp(a) to interact directly with plasminogen receptors. In the present study, we demonstrate that Lp(a) can interact directly with plasminogen binding sites on monocytoid U937 cells and endothelial cells. The interaction of Lp(a) with these sites was time dependent, specific, saturable, divalent ion independent and temperature sensitive, characteristics of plasminogen binding to these sites. The affinity of plasminogen and Lp(a) for these sites also was similar (Kd = 1-3 μM), but Lp(a) bound to fewer sites (̴10-fold less). Both gangliosides and cell surface proteins with car- boxy-terminal lysyl residues, including enolase, a candidate plasminogen receptor, inhibited Lp(a) binding to U937 cells. Additionally, Lp(a) interacted with low affinity lipoprotein binding sites on these cells which also recognized LDL and HDL. The ability of Lp(a) to interact with sites on cells that recognize plasminogen may contribute to the pathogenetic consequences of high levels of circulating Lp(a).

 

  • References

  • 1 Dahlén GH, Berg K, Gillnas T, Ericson C. Lp(a) lipoprotein/pre-Bl-lipoprotein in Swedish middle-aged males and in patients with coronary heart disease. J Clin Genet 1975; 7: 334-341
    PubMedGoogle Scholar
  • 2 Koltringer P, Jurgens G. A dominant role of lipoprotein(a) in the investigation and evaluation of parameters indicating the development of cervical atherosclerosis. Atherosclerosis 1985; 58: 187-198
    CrossrefPubMedGoogle Scholar
  • 3 Rhodes GG, Dahlén GH, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA 1986; 256: 2540-2544
    CrossrefPubMedGoogle Scholar
  • 4 Hoefler G, Harnoncourt F, Paschke E, Mirti W, Pfeiffer KH, Kostner GM. Lipoprotein Lp(a). A risk factor for myocardial infarction Arteriosclerosis 1988; 8: 398-401
    CrossrefPubMedGoogle Scholar
  • 5 Moliterno DJ, Lange RA, Meidell RS, Willard JE, Leffert CC, Gerard RD, Boerwinkle E, Hobbs HH, Hillis LD. Relation of plasma lipoprotein(a) to infarct artery patency in survivors of myocardial infarction. Circulation 1993; 88: 935-940
    CrossrefPubMedGoogle Scholar
  • 6 Howard GC, Pizzo SV. Biology of disease: Lipoprotein(a) and its role in atherothrombotic disease. Lab Invest 1993; 69: 373-386
    PubMedGoogle Scholar
  • 7 Scanu AM. Structural basis for the presumptive atherothrombogenic action of lipoprotein(a). Facts and speculations Biochem Pharmacol 1993; 46: 1675-1680
    CrossrefPubMedGoogle Scholar
  • 8 McLean JW, Tomlinson JE, Kuang W-J, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-137
    CrossrefPubMedGoogle Scholar
  • 9 Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding of lipoprotein^) to immobilized fibrinogen and fibrin. Proc Natl Acad Sei USA 1989; 86: 3847-3851
    CrossrefPubMedGoogle Scholar
  • 10 Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 1990; 10: 240-245
    CrossrefPubMedGoogle Scholar
  • 11 Edelberg JM, Gonzalez-Gronow M, Pizzo SV. Lipoprotein(a) inhibition of plasminogen activation by tissue-type plasminogen activator. Thromb Res 1990; 57: 155-162
    CrossrefPubMedGoogle Scholar
  • 12 Karadi I, Kostner GM, Gries A, Nimpf J, Romics L, Malle E. Lipoprotein(a) and plasminogen are immunochemically related. Biochim Biophys Acta 1988; 960: 91-97
    CrossrefPubMedGoogle Scholar
  • 13 Edelberg JM, Gonzalez-Gronow M, Pizzo SV. Lipoprotein a inhibits strep-tokinase-mediated activation of human plasminogen. Biochemistry 1989; 28: 2370-2374
    CrossrefPubMedGoogle Scholar
  • 14 Kluft C, Jie AF H, Los P, de Wit E, Havekes L. Functional analogy between lipoprotein(a) and plasminogen in the binding to the kringle 4 binding protein, tetranectin. Biochem Biophys Res Commun 1989; 161: 427-433
    CrossrefPubMedGoogle Scholar
  • 15 Rouy D, Grailhe P, Nigon F, Chapman J, Anglés-Cano E. Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator: In vitro studies in a plasma milieu. Arteriosclerosis 1991; 11: 629-638
    CrossrefPubMedGoogle Scholar
  • 16 Miles LA, Dahlberg CM, Plow EF. The cell-binding domains of plasminogen and their function in plasma. J Bio Chem 1988; 263: 11928-11934
    PubMedGoogle Scholar
  • 17 Gonzalez-Gronow M, Edelberg JM, Pizzo SV. Further characterization of the cellular plasminogen binding site: Evidence that plasminogen 2 and lipoprotein(a) compete for the same site. Biochemistry 1989; 28: 2374-2377
    CrossrefPubMedGoogle Scholar
  • 18 Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF. A potential basis for the thrombotic risks associated with lipoprotein(a). Nature 1989; 339: 301-303
    CrossrefPubMedGoogle Scholar
  • 19 Hajjar KA, Gavish D, Breslow JL, Nachman RL. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-305
    CrossrefPubMedGoogle Scholar
  • 20 Ezratty A, Simon DI, Loscalzo J. Lipoprotein(a) binds to human platelets and attenuates plasminogen binding and activation. Biochemistry 1993; 32: 4628-4633
    CrossrefPubMedGoogle Scholar
  • 21 Snyder ML, Polacek D, Scanu AM, Fless GM. Comparative binding and degradation of lipoprotein(a) and low density lipoprotein by human monocyte derived macrophages. J Biol Chem 1992; 267: 339-346
    PubMedGoogle Scholar
  • 22 Kostner GM, Grillhofer HK. Lipoprotein(a) mediates high affinity low density lipoprotein association to receptor negative fibroblasts. J Biol Chem 1991; 266: 21287-21292
    PubMedGoogle Scholar
  • 23 Zioncheck TF, Powell LM, Rice GC, Eaton DL, Lawn RM. Interaction of recombinant apolipoprotein(a) and lipoprotein(a) with macrophages. J Clin Invest 1991; 87: 767-771
    CrossrefPubMedGoogle Scholar
  • 24 Havekes L, Vermeer BJ, Brugman T, Emeis J. Binding of Lp(a) to the low density lipoprotein receptor of human fibroblasts. FEBS Lett 1981; 132: 169-173
    CrossrefPubMedGoogle Scholar
  • 25 Armstrong V, Harrach B, Robenek H, Helmhold M, Walli AK, Seidel D. Heterogeneity of human lipoprotein Lp[a]: cytochemical and biochemical studies on the interaction of two Lp[a] species with the LDL receptor. J Lipid Res 1990; 31: 429-441
    PubMedGoogle Scholar
  • 26 Hofmann SL, Eaton DL, Brown MS, McConathy WJ, Goldstein JL, Hammer RE. Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice. J Clin Invest 1990; 85: 1542-1547
    CrossrefPubMedGoogle Scholar
  • 27 Haberland ME, Fless G, Scanu AM, Fogelman AM. Modification of Lp(a) by malondialdehyde leads to avid uptake by human monocyte-macrophages. Circulation 1989; 80 Suppl (Suppl. 02) 163
    PubMedGoogle Scholar
  • 28 Miller NE. Induction of low density lipoprotein receptor synthesis by high density lipoprotein in cultures of human skin fibroblasts. Biochim Biophys Acta 1978; 529: 131-139
    CrossrefPubMedGoogle Scholar
  • 29 Curtiss LK, Plow EF. Interaction of plasma lipoproteins with human platelets. Blood 1984; 64: 365-374
    PubMedGoogle Scholar
  • 30 Alexander JJ, Remedios M, Graham D. High density lipoprotein inhibits low density lipoprotein binding and uptake by bovine aortic endothelial cells. Angiology 1990; 41: 1065-1069
    CrossrefPubMedGoogle Scholar
  • 31 Virgolini I, Li S, Qiong Y, Banyai M, Koller E, Angelberger P, Sinzinger H. Binding of 111In-labeled HDL to platelets from normolipemic volunteers and patients with heterozygous familial hypercholesterolemia. Arterioscler. Thromb 1992; 12: 849-861
    PubMedGoogle Scholar
  • 32 Fless GM, Rolih CA, Scanu AM. Heterogeneity of human plasma lipoprotein^) Isolation and characterization of the lipoprotein subspecies and their apoproteins. J Biol Chem 1984; 259: 11470-11478
    PubMedGoogle Scholar
  • 33 Eaton DL, Fless GM, Kohr WJ, McLean JW, Xu QT, Miller CG, Lawn RM, Scanu AM. Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. Proc Natl Acad Sci USA 1987; 84: 3224-3228
    CrossrefPubMedGoogle Scholar
  • 34 Curtiss LK, Edgington TS. Immunochemical heterogeneity of human plasma high density lipoproteins. J Biol Chem 1985; 260: 2982-2993
    PubMedGoogle Scholar
  • 35 Basu SK, Brown MS, Ho YK, Havel RJ, Goldstein JL. Mouse macrophages synthesize and secrete a protein resembling apolipoprotein E. Proc Natl Acad Sci USA 1981; 78: 7545-7549
    CrossrefPubMedGoogle Scholar
  • 36 Markwell MA K, Haas SM, Bieber LL, Tolbert NE. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 1978; 87: 206-210
    CrossrefPubMedGoogle Scholar
  • 37 Deutsch DG, Mertz ET. Plasminogen: purification from human plasma by affinity chromatography. Science 1970; 170: 1095-1096
    CrossrefPubMedGoogle Scholar
  • 38 Shepherd J, Bedford DK, Morgan HG. Radioiodination of human low density lipoprotein: a comparison of four methods. Clin Chim Acta 1976; 66: 97-109
    CrossrefPubMedGoogle Scholar
  • 39 Hoover-Plow JL, Miles LA, Fless GM, Scanu AM, Plow EF. Comparison of the lysine binding functions of lipoprotein(a) and plasminogen. Biochemistry 1993; 32: 13681-13687
    CrossrefPubMedGoogle Scholar
  • 40 Young SG, Witztum JL, Casai DC, Curtiss LK, Bernstein S. Conservation of the low density lipoprotein receptor-binding domain of apoprotein B. Arteriosclerosis 1986; 6: 178-188
    CrossrefPubMedGoogle Scholar
  • 41 Miles LA, Plow EF. Binding and activation of plasminogen on the platelet surface. J Biol Chem 1985; 260: 4303-4311
    PubMedGoogle Scholar
  • 42 Levin EG, Marzec U, Anderson J, Harker LA. Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest. 1984 74. 1988
    PubMedGoogle Scholar
  • 43 Ho YK, Brown MS, Kayden HJ, Goldstein JL. Binding, internalization, and hydrolysis of low density lipoprotein in long-term lymphoid cell lines from a normal subject and a patient with homozygous familial hypercholesterolemia. J Exp Med 1976; 144: 444-455
    CrossrefPubMedGoogle Scholar
  • 44 Goldstein JL, Basu SK, Brunschede GY, Brown MS. Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminogly- cans. Cell 1976; 7: 85-95
    CrossrefPubMedGoogle Scholar
  • 45 Miles LA, Levin EG, Plescia J, Collen D, Plow EF. Plasminogen receptors, urokinase receptors and their modulation on human endothelial cells. Blood 1988; 72: 628-635
    PubMedGoogle Scholar
  • 46 Hajjar KA, Harpel PC, Jaffe EA, Nachman RL. Binding of plasminogen to cultured human endothelial cells. J Biol Chem 1986; 261: 11656-11662
    PubMedGoogle Scholar
  • 47 Via DP, Plant AC, Craig IF, Gotto Jr AM, Smith LC. Metabolism of normal and modified low-density lipoproteins by macrophage cell lines of murine and human origin. Biochim Biophys Acta 1985; 833: 417-428
    CrossrefPubMedGoogle Scholar
  • 48 Hayashi K, Dojo S, Hirata H, Ohtani H, Nakashima K, Nishio E, Kurushima H, Saeki M, Kajiyama G. Metabolic changes in LDL receptors and an appearance of scavenger receptors after phorbol ester-induced differentiation of U937 cells. Biochim Biophys Acta 1991; 1082: 152-160
    CrossrefPubMedGoogle Scholar
  • 49 Miller NE, Weinstein DB, Carew TE, Koschinsky T, Steinberg D. Interaction between high density and low density lipoproteins during uptake and degradation by cultured human fibroblasts. J Clin Invest 1977; 60: 78-88
    CrossrefPubMedGoogle Scholar
  • 50 Miles LA, Dahlberg CM, Levin EG, Plow EF. Gangliosides interact directly with plasminogen and urokinase and may mediate binding of these fibrinolytic components to cells. Biochemistry 1989; 28: 9337-9343
    CrossrefPubMedGoogle Scholar
  • 51 Miles LA, Dahlberg CM, Plescia J, Felez J, Kato K, Plow EF. Role of cell-surface lysines in plasminogen binding to cells: identification of alpha-enolase as a candidate plasminogen receptor. Biochemistry 1991; 30: 1682-1691
    CrossrefPubMedGoogle Scholar
  • 52 Miles LA, Plow EF. Plasminogen receptors: Ubiquitous sites for cellular regulation of fibrinolysis. Fibrinolysis 1988; 2: 61-71
    PubMedGoogle Scholar
  • 53 Kojima S, Harpel PC, Rifkin DB. Lipoprotein (a) inhibits the generation of transforming growth factor β: An endogenous inhibitor of smooth muscle cell migration. J Cell Biol 1991; 113: 1439-1445
    CrossrefPubMedGoogle Scholar
  • 54 Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor betal like molecule by plasmin during co-culture. J Cell Biol 1989; 109: 309-315
    CrossrefPubMedGoogle Scholar
  • 55 Scanu AM, Miles LA, Pfaffinger D, Fless GM, Jackson E, Hoover-Plow JL, Brunck T, Plow EF. Rhesus monkey Lp(a) binds to lysine-Sepharose and U 937 monocytoid cells less efficiently than human Lp(a) Evidence for a dominant role of kringle 437. J Clin Invest 1993; 91: 283-291
    CrossrefPubMedGoogle Scholar
  • 56 Virgolini I, Li S, Qiong Y, Roller E, Banyai M, Angelberger P, Sinzinger H. Binding of 111In-labeled LDL to platelets of normolipemic volunteers and patients with heterozygous familial hypercholesterolemia. Arterioscler Thromb 1993; 13: 536-547
    CrossrefPubMedGoogle Scholar
  • 57 Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991; 64: 841-848
    CrossrefPubMedGoogle Scholar
  • 58 Leerink CB, Duif P, Gimpel JA, Kortlandt W, Bouma BN, van Rijn HJ M. Lysine-binding heterogeneity of Lp(a): Consequences for fibrin binding and inhibition of plasminogen activation. Thromb Haemost 1992; 68: 185-188
    Article in Thieme ConnectPubMedGoogle Scholar
  • 59 Lawn RM, Wade DP, Hammer RE, Chiesa G, Verstuyft JG, Rubin EM. Atherogenesis in transgenic mice expressing human apolipoprotein(a). Nature 1992; 360: 670-672
    CrossrefPubMedGoogle Scholar