Non-anticoagulant functions of heparin and heparan sulfate

Summary

Heparin is known to bind a large number of proteins not involved in anticoagula-tion, such as growth factors, adhesive proteins of the extracellular matrix, viral coat proteins and other enzymes and proteins. In vivo predominantly heparan sulfate – the most ubiquitous cell surface glycosaminoglycan – takes the functional role of heparin. Structural features, sources and non-anticoagulant func-tions of heparin and heparan sulfate proteoglycan are described. The functional diversity of heparin and heparan sulfate is reviewed in the following sections: (I) heparin and heparan sulfate as partners in fibroblast growth factor action, (II) antiproliferative effects of heparan sulfate and heparin, (III) cell surface heparan sulfate as extracellular matrix receptor and coreceptor, (IV) proteoheparan sulfate in central and peripheral nervous system, (V) role of proteoheparan sulfate in binding and uptake of lipoproteins, (VI) virus and spirochete binding to heparin and heparan sulfate.

Keywords

Proteoheparan sulfate - heparin - inhibition of proliferation - growth factor binding - extracellular matrix receptors

• REFERENCES

• 1 Jorpes E. The chemistry of heparin. Bio-chem J 1935; 29: 1817-24
• 2 Hirsch H. Heparin. N Engl J Med 1991; 324: 1565-72
• 3 Lee MK, Lander AD. Analysis of affinity and structural selectivity in the binding of proteins to glycosaminoglycans: development of a sensitive electrophoretic approach. Proc Natl Acad Sci 1991; 88: 2768-72
• 4 Lindahl U, Kusche M, Lidholt K, Oscarsson LG. Biosynthesis of heparin and heparan sulfate. Ann New York Acad Sci 1989; 556: 36-50
• 5 Schmidt A, Lemming G, Yoshida K, Buddecke E. Molecular organization and antiproliferative domains of arterial tissues heparan sulfat. Eur J Cell Biol 1992; 59: 322-8
• 6 Schmidt A, Yoshida K, Buddecke E. The antiproliferative activity of arterial heparan sulfate resides in domains enriched with 2-O-sulfated uronic acid residues. J Biol Chem 1992; 267: 19242-7
• 7 Carey DJ, Stahl RC. Identification of a lipid-anchored heparan sulfate proteoglycan in Schwann cells. J Cell Biol 1990; 111: 2053-62
• 8 Clement B, Segui-Real B, Hassel JR. et al. Identification of acell surface-binding protein for the core protein of the basement membrane proteoglycan. J Biol Chem 1989; 264: 12467-71
• 9 Bernfield M, Kokenyesi R, Kato M. et al. Biology of the syndecans: A family of transmembrane heparan sulfate proteoglycans. Annu Rev Cell Biol 1992; 8: 365-93
• 10 Kjellén L, Lindahl U. Proteoglycans; Structures and interactions. Annu Rev Biochem 1991; 60: 443-75
• 11 Zhou F, Höök T, Thompson JA, Höök M. Heparin protein interactions. In: Heparin and Related Polysaccharides. Lane DA, Björk I, Lindahl U. (eds). New York: Plenum Press; 1992: 141-53
• 12 Aviezer D, Levy E, Safran M. et al. Differential structural requirements of heparin and heparan sulfate proteoglycans that promote binding of basic fibroblast growth factor to its receptor. J Biol Chem 1994; 269: 114-21
• 13 Burgess WH, Maciag T. The heparin-bind-ing fibroblast growth factor family of proteins. Annu Rev Biochem; 1989; 58: 575-606
• 14 Shworak NW, Kojima T, Rosenberg RD. Isolation and characterization of ryudocan and syndecan heparan sulfate proteoglycans core proteins and cDNAs from a rat endothelial cell line Haemostasis. 1993; 23: 161-76
• 15 Pierce A, Lyon M, Hampson IN. et al. Molecular cloning of the major cell surface heparan sulfate proteoglycan from rat liver. J Biol Chem 1992; 267: 3894-900
• 16 Carey DC, Evans DM, Stahl RAC. et al. Molecular cloning and characterization of N-syndecan, a novel transmembrane heparan sulfate proteoglycan. J Cell Biol 1992; 117: 191-201
• 17 Baciu PC, Howard WB, Goetinck PF. Prediction of a novel integral membrane proteoglycan core protein related to syndecan and fibroglycan. J Cell Biol 1991; 115: 125a
• 18 Andres JL, Rönnstrand L, Cheifetz S, Massagué J. Purification of the transforming growth factor-ß (TGF-ß) binding proteoglycan betaglycan. J Biol Chem 1991; 266: 23282-7
• 19 Fransson LA, Carlstedt I, Cöster L, Malmström A. Binding of transferin to the core protein of fibroblast proteoheparan sulfate. Proc Natl Acad Sci. USA 1984; 81: 5657-61
• 20 Brown TA, Bouchard TSt., John T. et al. Human keratinocytes express a new CD44 core protein (CD44E) as a heparan sulfate intrinsic membrane proteoglycan with additional exons. J Cell Biol 1991; 113: 207-21
• 21 Lories V, Cassiman JJ, Van den Berghe H, David G. Differential expression of cell surface heparan sulfate proteoglycans in human mammary epithelial cells and lung fibroblasts. J Biol Chem 1992; 267: 1116-22
• 22 Schmidt A, Buddecke E. Bovine arterial smooth muscle cells synthesize two functionally different proteoheparan sulfate species. 1990; 189: 269-75
• 23 Murdoch AD, Dodge GR, Cohen I. et al. Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). J Biol Chem 1992; 267: 8544-57
• 24 Maccarana M, Casu B, Lindahl U. Minimal sequence in heparin/heparan sulfate required for binding of basic fibroblast growth factor. J Biol Chem 1993; 268: 23898-905
• 25 Tyrrell DJ, Ishihara M, Rao N. et al. Structure and biological activities of a heparin-derived hexasaccharide with high affinity for basic fibroblast growth factor. J Biol Chem 1993; 268: 4684-89
• 26 Turnbull JE, Fernig DG, Ke Y. et al. Identification of the basic fibroblast growth factor binding sequence in fibroblast heparan sulfate. J Biol Chem 1992; 267: 10337-41
• 27 Gallagher JT, Turnbull JE. Heparan sulphate in the binding and activation of basic fibroblast growth factor. Glycobiology 1992; 2: 523-8
• 28 Walker A, Turnbull JE, Gallagher JT. Specific heparan sulfate saccharides mediate the activity of basic fibroblast growth factor. J Biol Chem 1994; 269: 931-5
• 29 Springer BA, Pantoliano MW, Barbera FA. et al. Identification and concerted function of two receptor binding surfaces on basic fibroblast growth factor required for mito-genesis. J Biol Chem 1994; 269: 26879-84
• 30 Schmidt A, Buddecke E. Cell-associated proteoheparan sulfate from bovine arterial smooth muscle cells. Exp Cell Res 1988; 178: 242-53
• 31 Fritze LMS, Reilly CF, Rosenberg RD. An antiproliferative heparan sulfate species produced by postconfluent smooth muscle cells. J Cell Biol 1985; 100: 1041-9
• 32 Clowes AW, Karnovsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature 1977; 265: 625-6
• 33 More RS, Brack MJ, Gerschlick AH. Heparin after angioplasty: an unresolved issue. Eur Heart J 1993; 14: 1543-7
• 34 Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation 1992; 84: 1426-36
• 35 Fedarko NS, Conrad HE. A unique heparan sulfate in the nuclei of hepatocytes: structural changes with the growth state of the cells. J Cell Biol 1986; 102: 587-99
• 36 Karnovsky MJ, Wright jr TC , Castellot jr JJ. et al. Heparin heparan sulfate, smooth muscle cells and atherosclerosis. Ann N Y Acad Sci 1989; 556: 268-81
• 37 Guimond S, Maccarana M, Olwin BB. et al. Activating and inhibitory heparin sequences for FGF-2 (basic FGF). J Biol Chem 1993; 268: 23906-14
• 38 McCaffrey TA, Falcone DJ, Brayton CF. et al. Transforming growth factor-ß activity is potentiated by heparin via dissociating of the transforming growth factor-ß/2-macroglobu-lin inactive complex. J Cell Biol 1989; 109: 441-8
• 39 Goodman LV, Majack RA. Vascular smooth muscle cells express distinct transforming growth factor-ß receptor phenotypes as a function of cell density in culture. J Biol Chem 1989; 264: 5241-4
• 40 Grainger DJ, Witchell CM, Watson JV. et al. Heparin decreases the rate of proliferation of rat vascular smooth muscle cells by releasing transforming growth factor beta-like activity from serum. Cardiovasc Res 1993; 27: 2238-47
• 41 Pukac LA, Ottlinger ME, Karnovsky MJ. Heparin suppresses specific second messenger pathways for protooncogene expression in rat vascular smooth muscle cells. J Biol Chem 1992; 267: 3707-11
• 42 Bennett MR, Littlewood TD, Hancock DC. et al. Down-regulation of the c-myc protooncogene in inhibition of vascular smooth muscle cell proliferation: a signal for growth arrest?. Biochem J 1994; 302: 701-8
• 43 Hamno M, Bauters C, Wernert N. et al. Heparin does not inhibit oncogene induction in rabbit aorta following balloon denudation. Cardiovasc Res 1993; 27: 1209-13
• 44 Skaletz-Rorowski A, Schmidt A, Breithardt G, Buddecke E. Heparin-induced overex-pression of basic fibroblast growth factor, basic fibroblast growth factor receptor and cell-associated proteoheparan sulfate in cultured coronary smooth muscle cells. Arte-rioscl Thromb Vasc Biol (in press)
• 45 Koda JE, Bernfield M. Heparan sulfate proteoglycans from mouse mammary epithelial cells: basal extracellular proteoglycans bind specifically to native type I collagen fibrils. J Biol Chem 1984; 259: 11763-70
• 46 Saunders S, Bernfield M. Cell surface proteoglycan binds mouse mammary eptithelial cells to fibronectin and behaves as a receptor for interstitial matrix. J Cell Biol 1988; 106: 423-30
• 47 Yoneda J, Saiki I, Igarashi Y. et al. Role of the heparin-binding domain of chimeric peptides derived from fibronectin in cell spreading and motility. Exp Cell Res 1995; 217: 169-79
• 48 Weber P, Zimmermann DR, Winterhalter KH, Vaughan L. Tenascin-C binds heparin by its fibronectin type III domain five. J Biol Chem 1995; 270: 4619-23
• 49 Ramasamy S, Lipke DW, McClain CJ, Hennig B. Tumor necrosis factor reduces proteoglycan synthesis in cultured endothelial cells. J Cell Physiol 1995; 162: 119-26
• 50 Salmivirta M, Mali M, Heino J. et al. A novel laminin binding form of syndecan-1 (cell surface proteoglycan) produced by syndecan-1 cDNA-transfected NIH-3T3 cells. Exp Cell Res 1994; 215: 180-8
• 51 Mayer U, Zimmermann K, Mann K. et al. Binding properties and protease stability of recombinant human nidogen. Eur J Biochem 1995; 227: 681-6
• 52 Sun X, Mosher DF, Rapraeger A. Heparan sulfate-mediated binding of epithelial cell surface proteoglycan to thrombospondin. J Biol Chem 1989; 264: 2885-9
• 53 Marinides GN, Suchard SJ, Mookerjee BK. Role of thrombospondin in mesangial cell growth: possible existence of an autocrine feedback growth circuit. Kidney Int 1994; 46: 350-7
• 54 Karthikeyan L, Flad M, Engel M. et al. Im-munocytochemical and in situ hybridization studies in the heparan sulfate proteoglycan, glypican, in nervous tissue. J Cell Sci 1994; 107: 3213-22
• 55 Tsen G, Halfter W, Kroger S, Cole GJ. Agrin is a heparan sulfate proteoglycan. J Biol Chem 1995; 270: 3392-9
• 56 Small DH, Reed G, Whitefield B, Nurcombe V. Cholinergic regulation of neurite outgrowth from isolated chick sympatheti neurons in culture. J Neurosci 1995; 15: 144-51
• 57 Lafont F, Prochiantz A, Valenza C. et al. Defined glycosaminoglycan motifs have opposite effects on neuronal polarit in vitro. Dev Biol 1994; 165: 453-68
• 58 Sekiguchi RT, Potter-Perigo S, Braun K. et al. Characterization of proteoglycans synthesized by murine embryonal carcinom cells (P19) reveals increased expression of per-lecan (heparan sulfate proteoglycan) during neuronal differentiation. J Neurosci Res 1994; 38: 670-86
• 59 Peng HB, Ali AA, Dai Z. et al. The role of heparin binding growth associated molecule (HB-GAM) in the postsynaptic induction in cultured muscle cells. J Neurosci 1995; 15: 3027-38
• 60 Beisiegel U, Weber W, Bengtsson-Olive-crona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci USA 1991; 88: 8342-6
• 61 Roskams T, Moshage H, De-Vos R. et al. Heparan sulfate pro-teoglycan expression in normal human liver. Hepatology 1995; 21: 950-8
• 62 Ji ZS, Brecht WJ, Miranda RD. et al. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem 1993; 268: 10160-7
• 63 Nykjaer A, Nielsen M, Lookene A. et al. A carboxyl-terminal fragment of lipoprotein lipase binds to the low density lipoprotein receptor related protein and inhibits lipase-mediated uptake of lipoprotein in cells. J Biol Chem 1994; 269: 31747-55
• 64 Ji ZS, Mahley RW. Lactoferrin binding to heparan sulfate proteoglycans and the LDL receptor-related protein. Further evidence supporting the importance of direct binding of remnant lipoproteins to HSPG. Arterio-scler Thromb 1994; 14: 2025-31
• 65 Mulder M, Lombardi P, Jansen H. et al. Heparan sulphate proteoglycans are involved in the lipoprotein lipase-mediated enhancement of the cellular binding of very low density and low density lipoproteins. Biochem Biophys Res Commun 1992; 185: 582-7
• 66 Williams KJ, Fless GM, Petrie KA. et al. Mechanisms by which lipoprotein lipase alters cellular metabolism of lipoprotein (a), low density lipoprotein, and nascent lipoproteins. J Biol Chem 1992; 267: 13284-92
• 67 Roderiquez G, Oravecz T, Yanagishita M. et al. Mediation of human immunodeficiency virus type 1 binding to interaction of cell surface heparan sulfate proteoglycans with the V3 region of envelope gpl20-gp41. J Virol 1995; 69: 2233-9
• 68 Newburg DS, Linhardt RJ, Ampofo SA, Yolken RH. Human milk glycosaminogly-cans inhibit HIV glycoprotein gpl20 binding to its host cell CD4 receptor. J Nutr 1995; 125: 419-24
• 69 Shiek MT, WuDunn D, Montgomary RI. et al. Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J Cell Biol 1992; 116: 1273-81
• 70 Leong JM, Morrissey PE, Ortega-Barria E. et al. Hemagglutination and proteoglycan binding of the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun 1995; 63: 874-83
• 71 Brown KJ, Parish CR. Histidine-rich glycoprotein and platelet factor 4 mask heparan sulfate proteoglycans recognized by acidic and basic fibroblast growth factor. Biochemistry 1994; 33: 13918-27
• 72 Spring J, Goldberger OA, Jenkins NA. et al. Mapping of the syndecan genes in the mouse: linkage with members of the myc gene family. Genomics 1994; 21: 597-601
• 73 Schriever C, Schmidt A, Breithardt G, Buddecke E. Human recombinant insulin-like growth factor I and II stimulate the expression of basic fibroblast growth factor but supprsses the division of bovine coronary smooth muscle cells. Atherosclerosis (in press) .
• 74 Kovalszky H, Gallai M, Armbrust T, Rama-dori G. Syndecan-1 gene expression in isolated rat liver cells (hepatocytes, Kupffer cells, endothelial and Ito cells). Biochem Biophys Res Commun 1994; 204: 944-9
• 75 Kim CW, Goldberger OA, Gallo RL, Bern-field M. Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue-, and development-specific patterns. Mol Biol Cell 1994; 5: 797-805
• 76 Wang ZH, Manabe T, Ohshio G. et al. Im-munohistochemical study of heparan sulfate proteoglycan in adenocarcinomas of the pancreas. Pancreas 1994; 9: 758-63
• 77 Schmidt A, Skaletz-Rorowski A, Breithardt G, Buddecke E. Growth status-dependent changes of bFGF compartmentalization and heparan sulfate structure in arterial smooth muscle cells. Eur J Cell Biol 1995; 67: 130-5