Download PDF
Thromb Haemost 2006; 95(01): 142-150
DOI: 10.1160/TH05-07-0505
Cellular Proteolysis and Oncology
Schattauer GmbH

Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells

Benoît Ho-Tin-Noé
1   INSERM U698, Paris, France
2   Université Paris Denis Diderot, Paris, France
,
Olivier Meilhac
1   INSERM U698, Paris, France
2   Université Paris Denis Diderot, Paris, France
,
Patrick Rossignol
1   INSERM U698, Paris, France
2   Université Paris Denis Diderot, Paris, France
,
H. Roger Lijnen
3   Center for Molecular and Vascular Biology, Katholieke Universitet Leuven, Belgium
,
Eduardo Anglés-Cano
1   INSERM U698, Paris, France
2   Université Paris Denis Diderot, Paris, France
› Author AffiliationsFinancial support: This study was funded by the INSERM and grants Adrienne et Pierre Sommer from the Fondation de France to E AC, and project 04CV from the Leducq Foundation.
Further Information

Publication History

Received 19 July 2005

Accepted after resubmission 01 November 2005

Publication Date:
28 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Because of its structural homology with plasminogen, the apolipoprotein(a) [apo(a)] component of the athero-thrombogenic lipoprotein(a) [Lp(a)] particle inhibits plasminogen binding and activation onto fibrin as well as the subsequent fibrinolysis. In a similar manner, apo(a) may also interfere with plasmin(ogen)-induced cell detachment and apoptosis of adherent cells. To investigate this hypothesis, we studied the effect of a recombinant apo(a) [r-apo(a)] on plasminogen activation-induced apoptosis of vascular smooth muscle cells (VSMCs) and fibroblasts-like CHO-K1 cells. We demonstrate for the first time that apo(a) displays a concentration-dependent biphasic, enhancing/preventing effect on plasmin(ogen) induced cell detachment of VSMCs and CHO-K1 cells. Our results show that r-apo(a) binds to these cells with higher affinity than plasminogen [Kd = 0.9 ± 0.2 µM for plasminogen, Kd = 1.77 ± 0.34 nM for r-apo(a)] in a lysine-dependent manner. At high r-apo(a)/plasminogen ratios, their competitive interaction results in a partial inhibition of plasminogen activation by cell-bound t-PA. As a consequence, r-apo(a) prevents plasmin(ogen)-induced cell detachment and apoptosis. Surprisingly,at low r-apo(a)/plasminogen ratios,an enhancement in plasmin(ogen)-induced cell detachment and apoptosis was observed. This effect was shown to be “plasmin-selective” as r-apo(a) was unable to potentiate cell detachment induced by human neutrophil elastase and trypsin. Altogether these data are consistent with a new mechanism of apo(a)/plasmin(ogen) interactions that may contribute to the atherothrombogenic potential of Lp(a).

Keywords

Apolipoprotein(a) - cell detachment-induced apoptosis - plasminogen - vascular smooth muscle cells - CHO-K1 cells
 

  • References

  • 1 Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease Meta-analysis of prospective studies. Circulation 2000; 102: 1082-5.
    CrossrefPubMedGoogle Scholar
  • 2 Eaton DL, Fless GM, Kohr WJ. et al. Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. Proc Natl Acad Sci US A 1987; 84: 3224-8.
    CrossrefPubMedGoogle Scholar
  • 3 McLean JW, Tomlinson JE, Kuang WJ. et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-7.
    CrossrefPubMedGoogle Scholar
  • 4 Ernst A, Helmhold M, Brunner C. et al. Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a). J Biol Chem 1995; 270: 6227-34.
    CrossrefPubMedGoogle Scholar
  • 5 Hervio L, Durlach V, Girard-Globa A. et al. Multiple binding with identical linkage: a mechanism that explains the effect of lipoprotein(a) on fibrinolysis. Biochemistry 1995; 34: 13353-8.
    CrossrefPubMedGoogle Scholar
  • 6 Rouy D, Grailhe P, Nigon F. et al. Lipoprotein(a) impairs generation of plasmin byfibrin-bound tissue-type plasminogen activator In vitro studies ina plasma milieu. Arterioscler Thromb 1991; 11: 629-38.
    CrossrefPubMedGoogle Scholar
  • 7 Miles LA, Fless GM, Levin EG. et al. A potential basis for the thrombotic risks associated with lipoprotein(a). Nature 1989; 339: 301-3.
    CrossrefPubMedGoogle Scholar
  • 8 Hajjar KA, Gavish D, Breslow JL. et al. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-5.
    CrossrefPubMedGoogle Scholar
  • 9 Boonmark NW, Lou XJ, Yang ZJ. et al. Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice. J Clin Invest 1997; 100: 558-64.
    CrossrefPubMedGoogle Scholar
  • 10 Soulat T, Loyau S, Baudouin V. et al. Evidence that modifications of Lp(a) in vivo inhibit plasmin formation on fibrin--a study with individual plasmas presenting natural variations of Lp(a). Thromb Haemost 1999; 82: 121-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Kronenberg F, Kronenberg MF, Kiechl S. et al. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation 1999; 100: 1154-60.
    CrossrefPubMedGoogle Scholar
  • 12 Pepin JM, O’Neil JA, Hoff HF. Quantification of apo[a] and apoB in human atherosclerotic lesions. J Lipid Res 1991; 32: 317-27.
    PubMedGoogle Scholar
  • 13 Rath M, Niendorf A, Reblin T. et al. Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients. Arteriosclerosis 1989; 09: 579-92.
    CrossrefPubMedGoogle Scholar
  • 14 Zambrelli E, Emanuele E, Marcheselli S. et al. Apo(a) size in ischemic stroke: relation with subtype and severity on hospital admission. Neurology 2005; 64: 1366-70.
    CrossrefPubMedGoogle Scholar
  • 15 Longenecker JC, Klag MJ, Marcovina SM. et al. High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients. J Am Soc Nephrol 2005; 16: 1794-802.
    CrossrefPubMedGoogle Scholar
  • 16 Bot I, von der Thusen JH, Donners MM. et al. Serine protease inhibitor Serp-1 strongly impairs atherosclerotic lesion formation and induces a stable plaque phenotype in ApoE-/-mice. Circ Res 2003; 93: 464-71.
    CrossrefPubMedGoogle Scholar
  • 17 Meilhac O, Ho-Tin-Noe B, Houard X. et al. Pericellular plasmin induces smooth muscle cell anoikis. FASEB J 2003; 17: 1301-1303.
    CrossrefPubMedGoogle Scholar
  • 18 Reijerkerk A, Mosnier LO, Kranenburg O. et al. Amyloid endostatin induces endothelial cell detachment by stimulation of the plasminogen activation system. Mol Cancer Res 2003; 01: 561-8.
    PubMedGoogle Scholar
  • 19 Rossignol P, Ho-Tin-Noe B, Vranckx R. et al. Protease-nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem 2004; 279: 10346-56.
    CrossrefPubMedGoogle Scholar
  • 20 Ho-Tin-Noe B, Rojas G, Vranckx R. et al. Functional hierarchy of plasminogen kringles 1 and 4 in fibrinolysis and plasmin-induced cell detachment and apoptosis. Febs J 2005; 272: 3387-400.
    CrossrefPubMedGoogle Scholar
  • 21 Syrovets T, Thillet J, Chapman MJ. et al. Lipoprotein(a) is a potent chemoattractant for human peripheral monocytes. Blood 1997; 90: 2027-36.
    PubMedGoogle Scholar
  • 22 Galle J, Schneider R, Heinloth A. et al. Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: role of oxidative stress. Kidney Int 1999; 55: 1450-61.
    CrossrefPubMedGoogle Scholar
  • 23 Ichikawa T, Unoki H, Sun H. et al. Lipoprotein(a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo(a) transgenic rabbits. Am J Pathol 2002; 160: 227-36.
    CrossrefPubMedGoogle Scholar
  • 24 Kim JS, Chang JH, Yu HK. et al. Inhibition of angiogenesis and angiogenesis-dependent tumor growth by the cryptic kringle fragments of human apolipoprotein(a). J Biol Chem 2003; 278: 29000-8.
    CrossrefPubMedGoogle Scholar
  • 25 Pellegrino M, Furmaniak-Kazmierczak E, LeBlanc JC. et al. The apolipoprotein(a) component of lipoprotein(a) stimulates actin stress fiber formation and loss of cell-cell contact in cultured endothelial cells. J Biol Chem 2004; 279: 6526-33.
    CrossrefPubMedGoogle Scholar
  • 26 Battle T, Arnal JF, Challah M. et al. Selective isolation of rat aortic wall layers and their cell types in culture--application to converting enzyme activity measurement. Tissue Cell 1994; 26: 943-55.
    CrossrefPubMedGoogle Scholar
  • 27 Fleury V, Lijnen HR, Angles-Cano E. Mechanism of the enhanced intrinsic activity of single-chain urokinase-type plasminogen activator during ongoing fibrinolysis. J Biol Chem 1993; 268: 18554-9.
    PubMedGoogle Scholar
  • 28 Wiman B, Wallen P. Activation of human plasminogen by an insoluble derivative of urokinase Structural changes of plasminogen in the course of activation to plasmin and demonstration ofa possible intermediate compound. Eur J Biochem 1973; 36: 25-31.
    CrossrefPubMedGoogle Scholar
  • 29 Angles-Cano E, Loyau S, Cardoso-Saldana G. et al. A novel kringle-4 number-based recombinant apo[a] standard for human apo[a] phenotyping. J Lipid Res 1999; 40: 354-9.
    PubMedGoogle Scholar
  • 30 Tsurupa G, Ho-Tin-Noe B, Angles-Cano E. et al. Identification and characterization of novel lysine-independent apolipoprotein(a)-binding sites in fibrin (ogen) alphaC-domains. J Biol Chem 2003; 278: 37154-9.
    CrossrefPubMedGoogle Scholar
  • 31 Montes R, Paramo JA, Angles-Cano E. et al. Development and clinical application ofa new ELISA assay to determine plasmin-alpha2-antiplasmin complexes in plasma. Br J Haematol 1996; 92: 979-85.
    CrossrefPubMedGoogle Scholar
  • 32 Adamson AW. Physical Chemistry of Surfaces. New York: Wiley-Interscience Publication; 1992
    Google Scholar
  • 33 Kang C, Durlach V, Soulat T. et al. Lipoprotein(a) isoforms display differences in affinity for plasminogen-like binding to human mononuclear cells. Arterioscler Thromb Vasc Biol 1997; 17: 2036-43.
    CrossrefPubMedGoogle Scholar
  • 34 Plow EF, Herren T, Redlitz A. et al. The cell biology of the plasminogen system. Faseb J 1995; 09: 939-45.
    CrossrefPubMedGoogle Scholar
  • 35 Lupu F, Heim DA, Bachmann F. et al. Plasminogen activator expression in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1995; 15: 1444-55.
    CrossrefPubMedGoogle Scholar
  • 36 Clowes AW, Clowes MM, Au YP. et al. Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. Circ Res 1990; 67: 61-7.
    CrossrefPubMedGoogle Scholar
  • 37 Rickard KA, Taylor J, Rennard SI. Observations of development of resistance to detachment of cultured bovine bronchial epithelial cells in response to protease treatment. Am J Respir Cell Mol Biol 1992; 06: 414-20.
    CrossrefPubMedGoogle Scholar
  • 38 Mtairag el M, Houard X, Rais S. et al. Pharmacological potentiation of natriuretic peptide limits polymorphonuclear neutrophil-vascular cell interactions. Arterioscler Thromb Vasc Biol 2002; 22: 1824-31.
    CrossrefPubMedGoogle Scholar
  • 39 van der Hoek YY, Sangrar W, Cote GP. et al. Binding of recombinant apolipoprotein(a) to extracellular matrix proteins. Arterioscler Thromb 1994; 14: 1792-8.
    CrossrefPubMedGoogle Scholar
  • 40 Bihari-Varga M, Gruber E, Rotheneder M. et al. Interaction of lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycans from human aorta. Arteriosclerosis 1988; 08: 851-7.
    CrossrefPubMedGoogle Scholar
  • 41 Auerbach BJ, Cain W, Ansong M. et al. Lipoprotein lipase greatly enhances the retention of lipoprotein(a) to endothelial cell-matrix. Atherosclerosis 1999; 142: 89-96.
    CrossrefPubMedGoogle Scholar
  • 42 Klezovitch O, Edelstein C, Zhu L. et al. Apolipoprotein(a) binds via its C-terminal domain to the protein core of the proteoglycan decorin Implications for the retention of lipoprotein(a) in atherosclerotic lesions. J Biol Chem 1998; 273: 23856-65.
    CrossrefPubMedGoogle Scholar
  • 43 D’Angelo A, Geroldi D, Hancock MA. et al. The apolipoprotein(a) component of lipoprotein(a) mediates binding to laminin: contribution to selective retention of lipoprotein(a) in atherosclerotic lesions. Biochim Biophys Acta 2005; 1687: 1-10.
    CrossrefPubMedGoogle Scholar
  • 44 Bdeir K, Cane W, Canziani G. et al. Defensin promotes the binding of lipoprotein(a) to vascular matrix. Blood 1999; 94: 2007-19.
    PubMedGoogle Scholar
  • 45 Caird J, Burke M, Roberts G. et al. Apolipoprotein(A) expression in intracranial aneurysms. Neurosurgery 2003; 52: 854-8 discussion 858-9..
    CrossrefPubMedGoogle Scholar
  • 46 Papagrigorakis E, Iliopoulos D, Asimacopoulos PJ. et al. Lipoprotein(a) in plasma, arterial wall, and thrombus from patients with aortic aneurysm. Clin Genet 1997; 52: 262-71.
    PubMedGoogle Scholar
  • 47 Cushing GL, Gaubatz JW, Nava ML. et al. Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation. Arteriosclerosis 1989; 09: 593-603.
    CrossrefPubMedGoogle Scholar
  • 48 Fontaine V, Jacob MP, Houard X. et al. Involvement of the mural thrombus asa site of protease release and activation in human aortic aneurysms. Am J Pathol 2002; 161: 1701-10.
    CrossrefPubMedGoogle Scholar