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Thromb Haemost 1999; 81(04): 594-560
DOI: 10.1055/s-0037-1614531
Rapid Communication
Schattauer GmbH

Increased Expression of u-PA and u-PAR on Monocytes by LDL and Lp(a) Lipoproteins – Consequences for Plasmin Generation and Monocyte Adhesion

Florence Ganné
1   From the Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen
,
Marc Vasse
1   From the Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen
,
Jean-Louis Beaudeu
2   Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris
,
Jacqueline Peynet
2   Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris
,
Arnaud François
3   Service d’Anatomie et Cytologie Pathologiques, Hôpital C. Nicolle, Rouen
,
Jérôme Paysant
1   From the Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen
,
Bernard Lenormand
4   Unité fonctionnelle de Cytologie-Hématologie, Hôpital C. Nicolle, Rouen
,
Jean-Philippe Collet
5   Laboratoires de Biochimie et Ste Marie, Hôtel-Dieu, Paris
,
Jean-Pierre Vannier
1   From the Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen
,
Jeannette Soria
5   Laboratoires de Biochimie et Ste Marie, Hôtel-Dieu, Paris
,
Claudine Soria
1   From the Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen
6   INSERM U353, Hôpital St Louis, Paris, France
› Author Affiliations
Further Information

Publication History

Received 21 April 1998

Accepted after resubmission 05 January 1999

Publication Date:
09 December 2017 (online)

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Summary

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaque. As urokinase/urokinase-receptor (u-PA/u-PAR) is the trigger of a proteolytic cascade responsible for ECM degradation, we have examined the effect of atherogenic lipoproteins on monocyte surface expression of u-PAR and u-PA. Peripheral blood monocytes, isolated from 10 healthy volunteers, were incubated with 10 to 200 µg/ml of native or oxidised (ox-) atherogenous lipoproteins for 18 h and cell surface expression of u-PA and u-PAR was analysed by flow cytometry. Both LDL and Lp(a) induced a dose-dependent increase in u-PA (1.6-fold increase with 200 μg/ml of ox-LDL) and u-PAR [1.7-fold increase with 200 μg/ml of ox-Lp(a)]. There is a great variability of the response among the donors, some of them remaining non-responders (absence of increase of u-PA or u-PAR) even at 200 μg/ml of lipoproteins. In positive responders, enhanced u-PA/u-PAR is associated with a significant increase of plasmin generation (1.9-fold increase with 200 μg/ml of ox-LDL), as determined by an amidolytic assay. Furthermore, monocyte adhesion to vitronectin and fibrinogen was significantly enhanced by the lipoproteins [respectively 2-fold and 1.7-fold increase with 200 μg/ml of ox-Lp(a)], due to the increase of u-PAR and ICAM-1, which are receptors for vitronectin and fibrinogen. These data suggest that atherogenous lipoproteins could contribute to the development of atheromatous plaque by increasing monocyte adhesion and trigger plaque weakening by inducing ECM degradation.

 

  • References

  • 1 Castelli WB, Garrisson RJ, Wilson PWF, Abbott RD, Kaloudsian S, Kannel WB. The incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham study. JAMA 1986; 256: 2835-8.
    CrossrefPubMedGoogle Scholar
  • 2 Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR, Ordovas JM, Davis CE, Abolafia JM, Lippel K, Levy RI. Lipoprotein(a) and risk of coronary heart disease in men. JAMA 1994; 271: 999-1003.
    CrossrefPubMedGoogle Scholar
  • 3 Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witzum JL. Beyond cholesterol. Modification of low-density lipoprotein that increases its atherogenicity. N Engl J Med 1989; 320: 915-24.
    CrossrefPubMedGoogle Scholar
  • 4 Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 1979; 76: 333-7.
    CrossrefPubMedGoogle Scholar
  • 5 Bottalico LA, Keesler GA, Fless GM, Tabas I. Cholesterol loading of macrophages leads to marked enhancement of native lipoprotein(a) and apoprotein(a) internalization and degradation. J Biol Chem 1993; 268: 8569-73.
    PubMedGoogle Scholar
  • 6 Ross R. Cell biology of atherosclerosis. Ann Rev Physiol 1995; 57: 791-804.
    CrossrefPubMedGoogle Scholar
  • 7 Thomas CE, Jackson RL, Ohlweiler DF, Ku G. Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood mononuclear cells. J Lipid Res 1994; 35: 417-27.
    PubMedGoogle Scholar
  • 8 Lipton BA, Parthasarathy S, Ord VA, Clinton SK, Libby P, Rosenfeld ME. Components of the protein fraction of oxidized low density lipoprotein stimulate interleukin-1 alpha production by rabbit arterial macrophages-derived foam cells. J Lipid Res 1995; 36: 2232-42.
    PubMedGoogle Scholar
  • 9 Brand K, Banka CL, Nackman N, Terkeltaub RA, Fan ST, Curtis LK. Oxidized low density lipoprotein enhances lipopolysaccharide-induced tissue factor expression in human monocytes. Arterioscler Thromb 1994; 14: 790-7.
    CrossrefPubMedGoogle Scholar
  • 10 Davies MJ, Thomas AC. Plaque fissuring – the cause of acute myocardial infarction, sudden ischemic death and crescendo angina. Br Heart J 1985; 53: 353-73.
    CrossrefPubMedGoogle Scholar
  • 11 Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol 1997; 17: 1859-67.
    CrossrefPubMedGoogle Scholar
  • 12 Prediman K, Shah MD. Pathophysiology of plaque rupture and the concept of plaque stabilization. Cardiol Clin 1996; 14: 17-29.
    CrossrefPubMedGoogle Scholar
  • 13 Blasi F. Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness. Bioessays 1993; 15: 105-11.
    CrossrefPubMedGoogle Scholar
  • 14 Carmeliet P, Moons L, Lijnen R, Baes M, Lemaître V, Tipping P, Drew A, Eeckhout Y, Shapiro S, Lupu F, Collen D. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nature genetics 1997; 17: 439-44.
    CrossrefPubMedGoogle Scholar
  • 15 Waltz DA, Chapman HA. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J Biol Chem 1994; 269: 14746-50.
    PubMedGoogle Scholar
  • 16 Kanse SM, Kost C, Wilhem OG, Andreasen PA, Preissner KT. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp Cell Res 1996; 224: 344-53.
    CrossrefPubMedGoogle Scholar
  • 17 Waltz DA, Sailor LZ, Chapman HA. Cytokines induce urokinase-dependant adhesion of human myeloid cells. A regulatory role for plasminogen activator inhibitors. J Clin Invest 1993; 91: 1541-52.
    CrossrefPubMedGoogle Scholar
  • 18 Simon DI, Rao NK, Xu H, Wei Y, Majdic O, Ronne E, Kobzik L, Chapman HA. Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. Blood 1996; 88: 3185-94.
    PubMedGoogle Scholar
  • 19 Sitrin RG, Todd RF, Petty HR, Brock TG, Shollenberg SB, Albrecht E, Gyetko MR. The urokinase receptor (CD87) facilitates CD11b/CD18-mediated adhesion of human monocytes. J Clin Invest 1996; 97: 1942-51.
    CrossrefPubMedGoogle Scholar
  • 20 Languino LR, Plescia J, Duperray A, Brian AA, Plow EF, Geltosky JE, Altieri DC. Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1 dependent pathway. Cell 1993; 73: 1423-34.
    CrossrefPubMedGoogle Scholar
  • 21 Kamboh I M, Ferrel RE, Kottke BA. Expressed hypervariable polymorphism of apolipoprotein(a). Am J Hum Genet 1991; 49: 1063-74.
    PubMedGoogle Scholar
  • 22 Beaudeux JL, Césarini ML, Gardès-Albert M, Maclouf J, Merval R, Esposito B, Peynet J, Tedgui A. Native and γ radiolysis-oxidized lipoprotein(a) increase the adhesiveness of rabbit aortic endothelium. Atherosclerosis 1997; 132: 29-35.
    CrossrefPubMedGoogle Scholar
  • 23 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-75.
    PubMedGoogle Scholar
  • 24 Todd lll RF, Barnathan ES, Bohuslav J, Chapman HA, Cohen RL, Felez J, Howell A, Johnson JG, Knapp W, Kramer M, Miles LA, Nykjaer A, Ralfkiaer E, Schuren E. Leukocyte Typing V: White Cells Differentiation Antigens. In CD87 cluster workshop report. Schlossman S, Boumsell L, Gilks W. eds. New York: Oxford University Press; 1995: 932-7.
    Google Scholar
  • 25 Wiztum JL, Teinberg D. Role of oxidized LDL in atherogenesis. J Clin Invest 1991; 88: 1785-92.
    CrossrefPubMedGoogle Scholar
  • 26 Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndrome: Implications for plaque rupture. Circulation 1994; 90: 775-8.
    CrossrefPubMedGoogle Scholar
  • 27 Galis Z, Sukhova G, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci USA 1995; 92: 402-6.
    CrossrefPubMedGoogle Scholar
  • 28 Lee SW, Ellis V, Dichek DA. Characterization of plasminogen activation by glycosylphosphatidylinositol-anchored urokinase. J Biol Chem 1994; 269: 2411-8.
    PubMedGoogle Scholar
  • 29 Hsu HY, Hajjar DP, Faisal Khan KM Falcone DJ. Ligand binding to macrophages scavenger receptor-A induces urokinase-type plasminogen activator expression by a protein kinase-dependent signaling pathway. J Biol Chem 1998; 273: 1240-6.
    CrossrefPubMedGoogle Scholar
  • 30 Falcone DJ, McCaffrey TA, Haimovitz-Friedman A, Vergilio JA, Nichol-son AC. Macrophage and foam cell release of matrix-bound growth factors. Role of plasminogen activation. J Biol Chem 1993; 268: 11951-8.
    PubMedGoogle Scholar
  • 31 Ritchie H, Jamieson A, Booth NA. Peripheral blood monocyte synthesis of plasminogen activator inhibitor 2 in response to native and modified LDL. Thromb Haemost 1995; 74: 1521-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Tipping PG, Davenport P, Gallicchio M, Filonzi EL, Apostolopoulos J, Wojta J. Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulate its production by endothelial cells and vascular smooth muscle cells. Am J Pathol 1993; 143: 875-85.
    PubMedGoogle Scholar
  • 33 Smith EB, Thompson W. Fibrin as a risk factor in atherogenesis. Thromb Res 1994; 73: 1-19.
    CrossrefPubMedGoogle Scholar
  • 34 Dufourcq P, Louis H, Moreau C, Daret D, Boisseau MR, Lamazière JMD, Bonnet J. Vitronectin expression and interaction with receptors in smooth muscle cells from human atheromatous plaque. Arterioscler Thromb Vasc Biol 1998; 18: 168-76.
    CrossrefPubMedGoogle Scholar