Download PDF
Thromb Haemost 2002; 87(05): 880-887
DOI: 10.1055/s-0037-1613100
Review Article
Schattauer GmbH

Platelet Activation by the apoB/E Receptor-binding Domain of LDL

I. A. M. Relou
1   Laboratory for Thrombosis and Haemostasis, Department of Haematology, University of Utrecht, The Netherlands
,
G. Gorter
1   Laboratory for Thrombosis and Haemostasis, Department of Haematology, University of Utrecht, The Netherlands
,
J. M. H. van Rijn
2   Department of Clinical Chemistry, University Medical Center Utrecht, and Institute for Biomembranes, University of Utrecht, The Netherlands
,
N. J.-W. Akkerman
1   Laboratory for Thrombosis and Haemostasis, Department of Haematology, University of Utrecht, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 20 August 2001

Accepted after revision 01 February 2002

Publication Date:
11 December 2017 (online)

    Permissions and Reprints

Summary

Low density lipoprotein (LDL) increases the sensitivity of human platelets for agonists by activating p38MAPK. Antibody 4G3 disturbs apoB100 binding to the classical apoB/E receptor and inhibits LDLinduced p38MAPK activation, whereas an antibody against a distal domain on apoB100 has no effect. Peptide RLTRKRGLKLA mimics the binding domain of apoB100 called the B-site and activates platelet p38MAPK. Activation by B-site peptide is dose-dependent, transient and followed by desensitization, in accordance with receptor-mediated signalling. A scrambled peptide and a partially homologous peptide RKLRKRLLRDA mimicking the apoB/E receptor binding site of apoE in high density lipoprotein (HDL) also activate p38MAPK albeit 40% weaker, but an uncharged peptide lacks p38MAPK activating capacity. LDL and B-site peptide bind to the same binding sites and initiate similar signalling to p38MAPK and cytosolic phospholipase A2. Thus, LDL and to a lesser extent HDL activate platelets via specific domains in the protein moiety that recognize receptors of the LDL receptor family.

Keywords

LDL - platelets - p38MAPK - apoB100 - apoE
 

  • References

  • 1 Chatterton JE, Phillips ML, Curtiss LK, Milne R, Fruchart JC, Schumaker VN. Immunoelectron microscopy of low density lipoproteins yields a ribbon and bow model for the conformation of apolipoprotein B on the lipoprotein surface. J Lipid Res 1995; 36: 2027-37.
    PubMedGoogle Scholar
  • 2 Mahley RW, Innerarity TL, Pitas RE, Weisgraber KH, Brown JH, Gross E. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins. J Biol Chem 1977; 252: 7279-87.
    PubMedGoogle Scholar
  • 3 Weisgraber KH, Innerrarity TL, Mahley RW. Role of the lysine residues of plasma lipoproteins in high-affinity binding to cell surface receptors on human fibroblasts. J Biol Chem 1978; 253: 9053-62.
    PubMedGoogle Scholar
  • 4 Brown MS, Goldstein JL. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. Cell 1975; 06: 307-16.
    CrossrefPubMedGoogle Scholar
  • 5 Boren J, Lee I, Zhu W, Arnold K, Taylor S, Innerarity TL. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 1998; 101: 1084-93.
    CrossrefPubMedGoogle Scholar
  • 6 Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988; 240: 622-30.
    CrossrefPubMedGoogle Scholar
  • 7 Boren J, Lee I, Zhu W, Arnold K, Taylor S, Innerarity TL. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 1998; 101: 1084-93.
    CrossrefPubMedGoogle Scholar
  • 8 Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, Grundy SM. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987; 84: 6919-23.
    CrossrefPubMedGoogle Scholar
  • 9 Allen S, Khan S, Al-Mohanna F, Batten P, Yacoub M. Native low density lipoprotein-induced calcium transients trigger VCAM-1 and E-selectin expression in cultured human vascular endothelial cells. J Clin Invest 1998; 101: 1064-75.
    CrossrefPubMedGoogle Scholar
  • 10 Hackeng CM, Huigsloot M, Pladet MW, Nieuwenhuis HK, Rijn HJMv, Akkerman JWN. Low-density lipoprotein enhances platelet secretion via integrin-αIIbβ3-mediated signaling. Arterioscler Thromb Vasc Biol 1999; 19: 239-47.
    CrossrefPubMedGoogle Scholar
  • 11 Hackeng CM, Pladet MW, Akkerman JW, van Rijn HJ. Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125(FAK) in human platelets independent of integrin alphaIIb beta3. J Biol Chem 1999; 274: 384-8.
    CrossrefPubMedGoogle Scholar
  • 12 Surya II, Gorter G, Mommersteeg M, Akkerman JWN. Enhancement of platelet functions by low density lipoproteins. Biochim Biophys Acta 1992; 1165: 19-26.
    CrossrefPubMedGoogle Scholar
  • 13 Lyman S, Gilmore A, Burridge K, Gidwitz S, White II GC. Integrinmediated activation of focal adhesion kinase is independent of focal adhesion formation or integrin activation – Studies with activated and inhibitory β3 cytoplasmic domain mutants. J Biol Chem 1997; 272: 22538-47.
    CrossrefPubMedGoogle Scholar
  • 14 van Willigen G, Gorter G, Akkerman JWN. LDLs increase the exposure of fibrinogen binding sites on platelets and secretion of dense granules. Arterioscler Thromb 1994; 14: 41-6.
    CrossrefPubMedGoogle Scholar
  • 15 Pedreno J, de Castellarnau C, Cullare C, Sanchez J, Gomez JGerique, Ordonez JLlanos, Gonzalez FSastre. LDL binding sites on platelets differ from the “classical” receptor of nucleated cells. Arterioscler Thromb 1992; 12: 1353-62.
    CrossrefPubMedGoogle Scholar
  • 16 Riddell DR, Vinogradov DV, Stannard AK, Chadwick N, Owen JS. Identification and characterization of LRP8 (apoER2) in human blood platelets. J Lipid Res 1999; 40: 1925-30.
    PubMedGoogle Scholar
  • 17 Hackeng CM, Relou IA, Pladet MW, Gorter G, van Rijn HJ, Akkerman JW. Early platelet activation by low density lipoprotein via p38MAP kinase. Thromb Haemost 1999; 82: 1749-56.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogenactivated protein kinase signal transduction pathways. J Mol Med 1996; 74: 589-607.
    CrossrefPubMedGoogle Scholar
  • 19 Esterbauer H, Gebicki J, Puhl H, Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 1992; 13: 341-90.
    CrossrefPubMedGoogle Scholar
  • 20 Siess W, Zangl KJ, Essler M, Bauer M, Brandl R, Corrinth C, Bittman R, Tigyi G, Aepfelbacher M. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. Proc Natl Acad Sci USA 1999; 96: 6931-6.
    CrossrefPubMedGoogle Scholar
  • 21 Aviram M, Brook JG, Lees AM, Lees RS. Low density lipoprotein binding to human platelets: role of charge and of specific amino acids. Biochem Biophys Res Commun 1981; 99: 308-18.
    CrossrefPubMedGoogle Scholar
  • 22 Choudhri TF, Hoh BL, Zerwes HG, Prestigiacomo CJ, Kim SC, Connolly ESJ, Kottirsch G, Pinsky DJ. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest 1998; 102: 1301-10.
    CrossrefPubMedGoogle Scholar
  • 23 Milne RW, Theolis Jr. R, Verdery RB, Marcel YL. Characterization of monoclonal antibodies against human low density lipoprotein. Arteriosclerosis 1983; 03: 23-30.
    CrossrefPubMedGoogle Scholar
  • 24 Havel RJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 1955; 34: 1345-53.
    CrossrefPubMedGoogle Scholar
  • 25 Kramer RM, Roberts EF, Hyslop PA, Utterback BG, Hui KY, Jakubowski JA. Differential activation of cytosolic phospholipase A2 (cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2 independent of the mitogen-activated protein kinases ERK1/2. J Biol Chem 1995; 270: 14816-23.
    CrossrefPubMedGoogle Scholar
  • 26 Jacobs DS. Laboratory test handbook. Cleveland, U. S: Lexi-Comp inc; 1996
    Google Scholar
  • 27 Hackeng CM, Franke B, Relou IA, Gorter G, Bos JL, van Rijn HJ, Akkerman JW. Low-density lipoprotein activates the small GTPases Rap1 and Ral in human platelets. Biochem J 2000; 349: 231-8.
    CrossrefPubMedGoogle Scholar
  • 28 Desai K, Bruckdorfer KR, Hutton RA, Owen JS. Binding of apoE-rich high density lipoprotein particles by saturable sites on human blood platelet inhibits agonist-induced platelet aggregation. J Lipid Res 1989; 30: 831-40.
    PubMedGoogle Scholar
  • 29 Boren J, Lee I, Zhu W, Arnold K, Taylor S, Innerarity TL. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 1998; 101: 1084-93.
    CrossrefPubMedGoogle Scholar
  • 30 Law A, Scott J. A cross-species comparison of the apolipoprotein B domain that binds to the LDL receptor. J Lipid Res 1990; 31: 1109-20.
    PubMedGoogle Scholar
  • 31 Mahley RW, Weisgraber KH, Innerarity TL. Interaction of plasma lipoproteins containing apolipoproteins B and E with heparin and cell surface receptors. Biochim Biophys Acta 1979; 575: 81-91.
    CrossrefPubMedGoogle Scholar
  • 32 Olsson U, Camejo G, Olofsson SO, Bondjers G. Molecular parameters that control the association of low density lipoprotein apo B-100 with chondroitin sulphate. Biochim Biophys Acta 1991; 1097: 37-44.
    CrossrefPubMedGoogle Scholar
  • 33 Goldstein JL, Basu SK, Brown MS. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol 1983; 98: 241-60.
    PubMedGoogle Scholar
  • 34 Pedreno J, de Castellarnau C, Cullare C, Ortin R, Sanchez JL, Llopart R, Gonzalez FSastre. Platelet LDL receptor recognizes with the same apparent affinity both oxidized and native LDL. Evidence that the receptor-ligand complexes are not internalized. Arterioscler Thromb 1994; 14: 401-8.
    CrossrefPubMedGoogle Scholar
  • 35 Mazurov AV, Preobrazhensky SN, Leytin VL, Repin VS, Smirnov VN. Study of low density lipoprotein interaction with platelets by flow cytofluorimetry. FEBS Lett 1982; 137: 319-22.
    CrossrefPubMedGoogle Scholar
  • 36 Aviram M, Sirtori CR, Colli S, Maderna P, Morazzoni G, Tremoli E. Plasma lipoproteins affect platelet malondialdehyde and thromboxane B2 production. Biochem Med 1985; 34: 29-36.
    CrossrefPubMedGoogle Scholar
  • 37 Ardlie NG, Selley ML, Simons LA. Platelet activation by oxidatively modified low density lipoproteins. Atherosclerosis 1989; 76: 117-24.
    CrossrefPubMedGoogle Scholar
  • 38 Riddell DR, Graham A, Owen JS. Apolipoprotein E inhibits platelet aggregation through the L-arginine:nitric oxide pathway. Implications for vascular disease. J Biol Chem 1997; 272: 89-95.
    CrossrefPubMedGoogle Scholar
  • 39 Knott TJ, Rall SCJ, Innerarity TL, Jacobson SF, Urdea MS, Levy-Wilson B, Powell LM, Pease RJ, Eddy R, Nakai H. Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization. Science 1985; 230: 37-43.
    CrossrefPubMedGoogle Scholar
  • 40 Nazih H, Nazih FSanderson, Magret V, Caron B, Goudemand J, Fruchart JC, Delbart C. Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets. Arterioscler Thromb 1994; 14: 1321-6.
    CrossrefPubMedGoogle Scholar
  • 41 Pedreno J, Vila M, Masana L. Mechanisms for regulating platelet high density lipoprotein type 3 binding sites: evidence that binding sites are downregulated by a protein kinase C-dependent mechanism. Thromb Res 1999; 94: 33-44.
    CrossrefPubMedGoogle Scholar
  • 42 Kim DH, Iijima H, Goto K, Sakai J, Ishii H, Kim HJ, Suzuki H, Kondo H, Saeki S, Yamamoto T. Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J Biol Chem 1996; 271: 8373-80.
    CrossrefPubMedGoogle Scholar