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Thromb Haemost 1998; 79(03): 579-586
DOI: 10.1055/s-0037-1614949
Review Articles
Schattauer GmbH

Relation of Urokinase-Type Plasminogen Activator Expression to Presence and Severity of Atherosclerotic Lesions in Human Coronary Arteries

Joachim Kienast
1   Department of Internal Medicine, Section of Hematology/Oncology
,
Teresa Padró
1   Department of Internal Medicine, Section of Hematology/Oncology
,
Martin Steins
1   Department of Internal Medicine, Section of Hematology/Oncology
,
Chang-Xun Li
1   Department of Internal Medicine, Section of Hematology/Oncology
,
Kurt W. Schmid
2   Institute of Pathology
,
Dieter Hammel
3   Department of Cardiovascular Surgery, University of Muenster, Germany
,
Hans H. Scheld
3   Department of Cardiovascular Surgery, University of Muenster, Germany
,
Jürgen C. W. van de Loo
1   Department of Internal Medicine, Section of Hematology/Oncology
› Author Affiliations
Further Information

Publication History

Received 25 July 1997

Accepted after revision 29 October 1997

Publication Date:
07 December 2017 (online)

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Summary

Urokinase-type plasminogen activator (UPA) has been implicated in a broad spectrum of pathological processes – e.g. cell adhesion, migration and proliferation and matrix remodeling – that are considered important features of atherogenesis and plaque disruption. In this study, we have analyzed the content and expression of UPA in human coronary arteries and its relation to the presence and severity of atherosclerotic lesions. Segments of coronary arteries obtained from human heart explants (n = 15) were classified by the presence and types of atherosclerotic lesions. UPA was quantitatively determined in protein extracts of the intimal and medial layers. In situ hybridization and immunohistochemical analyses were performed on serial sections of representative tissue specimens. UPA was detected in the extracts as pro-UPA, UPA complexed to plasminogen activator inhibitor-1, or as otherwise inactive UPA antigen, but not in the active two-chain form. Both functional and total UPA were increased several-fold in extracts of advanced lesions, while the ratios of functional over total UPA showed the opposite trend suggesting enhanced UPA inactivation and turnover. UPA expression in early atherosclerotic lesions was particularly prominent in areas of proliferating SMCs in the abluminal part of the neointima, whereas in advanced lesions UPA was widely expressed in macrophage-rich areas adjacent to the rims and shoulder regions of the necrotic cores. The results strongly suggest a causal involvement of UPA in coronary atherogenesis and its clinical outcome.

 

  • References

  • 1 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
    CrossrefPubMedGoogle Scholar
  • 2 Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994; 94: 2493-503.
    CrossrefPubMedGoogle Scholar
  • 3 Libby P. Molecular basis of the acute coronary syndromes. Circulation 1995; 91: 2844-50.
    CrossrefPubMedGoogle Scholar
  • 4 Davis MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985; 53: 363-73.
    CrossrefPubMedGoogle Scholar
  • 5 Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulation of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6: 131-8.
    CrossrefPubMedGoogle Scholar
  • 6 Welgus HG, Campbell EJ, Curry JD, Eisen AZ, Senior RM, Wilhelm SM, Goldberg GI. Neutral metalloproteinases produced by human mononuclear phagocytes: enzyme profile, regulation and cellular differentiation. J Clin Invest 1990; 86: 1496-502.
    CrossrefPubMedGoogle Scholar
  • 7 Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis. Circulation 1990; 82 (Supp II): 47-59.
    PubMedGoogle Scholar
  • 8 Vassalli JD. The urokinase receptor. Fibrinolysis 1994; 8 (Suppl): 172-81.
    PubMedGoogle Scholar
  • 9 Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88: 1067-72.
    CrossrefPubMedGoogle Scholar
  • 10 Reuning U, Bang NU. Regulation of the urokinase-type plasminogen activator receptor on vascular smooth muscle cells is under control of thrombin and other mitogens. Arterioscler Thromb 1992; 12: 1161-70.
    CrossrefPubMedGoogle Scholar
  • 11 Lundgren CH, Sawa H, Sobel BE, Fujii S. Modulation of expression of monocyte/macrophage plasminogen activator activity and its implications for attenuation of vasculopathy. Circulation 1994; 90: 1927-34.
    CrossrefPubMedGoogle Scholar
  • 12 Odekon LE, Blasi F, Rifkin D. Requirement for receptor-bound urokinase in plasmin dependent cellular conversion of latent TGF-β to TGF-β. J Cell Physiol 1994; 158: 398-407.
    CrossrefPubMedGoogle Scholar
  • 13 Falcone DJ, McCaffrey TA, Haimovitz-Friedman A, Vergilio JA, Nicholson AC. Macrophage and foam cell release matrix-bound growth factors. Role of plasminogen activation. J Biol Chem 1993; 268: 11951-8.
    PubMedGoogle Scholar
  • 14 De Petro G, Copeta A, Barlati S. Urokinase-type and tissue-type plasminogen activators as growth factors of human fibroblasts. Exp Cell Res 1994; 213: 286-94.
    CrossrefPubMedGoogle Scholar
  • 15 Kanse SM, Kost C, Benzakour O, Kanthou C, Lijnen R, Preissner KT. Urokinase-type plasminogen activator in vasoproliferative disorders: Induction of vascular smooth muscle cell proliferation indicates a novel mechanism of action. Thromb Haemost 1997; Suppl: 582 (Abstract).
    PubMedGoogle Scholar
  • 16 Clowes AW, Clowes MM, Au YPT, Reidy MA, Belin D. 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
  • 17 More RS, Underwood MJ, Brack MJ, de Bono DP, Gershlick AH. Changes in vessel wall plasminogen activator activity and smooth muscle cell proliferation and activation after arterial injury. Cardiovasc Res 1995; 29: 22-6.
    CrossrefPubMedGoogle Scholar
  • 18 Reidy MA, Irvin C, Lindner V. Migration of arterial wall cells. Expression of plasminogen activators and inhibitors in injured rat arteries. Circ Res 1996; 78: 405-14.
    CrossrefPubMedGoogle Scholar
  • 19 Kenagy RD, Vergel S, Mattsson E, Bendeck M, Reidy MA, Clowes AW. The role of plasminogen, plasminogen activators and matrix metalloproteinases in primate arterial smooth muscle cell migration. Arterioscler Thromb Vasc Biol 1996; 16: 1373-82.
    CrossrefPubMedGoogle Scholar
  • 20 Carmeliet P, Collen D. Gene manipulation and transfer of the plasminogen and coagulation system in mice. Semin Thromb Hemostas 1996; 22: 525-42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Padró T, Emeis JJ, Steins M, Schmid KW, Kienast J. Quantification of plasminogen activators and their inhibitors in the aortic vessel wall in relation to the presence and severity of atherosclerotic disease. Arterioscler Thromb Vasc Biol 1995; 15: 893-902.
    CrossrefPubMedGoogle Scholar
  • 22 Lupu F, Heim DA, Bachmann F, Hurni M, Kakkar VV, Kruithof EKO. Plasminogen activator expression in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1995; 15: 1444-55.
    CrossrefPubMedGoogle Scholar
  • 23 Schneiderman J, Bordin GM, Engelberg I, Adar R, Seiffert D, Thinnes T, Bernstein EF, Dilley RB, Loskutoff D. Expression of fibrinolytic genes in atherosclerotic abdominal aortic aneurysm wall. J Clin Invest 1995; 96: 639-45.
    CrossrefPubMedGoogle Scholar
  • 24 Underwood MJ, de Bono DP. Increased fibrinolytic activity in the intima of atheromatous coronary arteries: protection at a price. Cardiovasc Res 1993; 27: 882-5.
    CrossrefPubMedGoogle Scholar
  • 25 Raghunath PN, Tomaszewski JE, Brady ST, Caron RJ, Okada SS, Barnathan ES. Plasminogen activator system in human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15: 1432-43.
    CrossrefPubMedGoogle Scholar
  • 26 Ronne E, Hoyer-Hansen G, Brünner N, Pedersen H, Rank F, Osborne CK, Clark GM, Dano K, Grondahl-Hansen J. Urokinase receptor in breast cancer tissue extracts. Enzyme-linked immunosorbent assay with a combination of mono- and polyclonal antibodies. Breast Cancer Res Treat 1995; 33: 199-207.
    CrossrefPubMedGoogle Scholar
  • 27 Camiolo SM, Siuta MR, Madeja JM. Improved medium for extraction of plasminogen activator from tissue. Prep Biochem 1982; 12: 297-305.
    PubMedGoogle Scholar
  • 28 Reilly JM, Sicard GA, Lucore CL. Abnormal expression of plasminogen activators in aortic aneurysmal and occlusive disease. J Cardiovasc Surg 1994; 19: 865-72.
    PubMedGoogle Scholar
  • 29 Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Kleuk DC. Measurement of protein using bicinchoninic acid. Anal Biochem 1985; 150: 76-85.
    CrossrefPubMedGoogle Scholar
  • 30 Pannell R, Gurewich V. Activation of plasminogen by single-chain urokinase or by two-chain urokinase. A demonstration that single-chain urokinase has a low catalytic activity. Blood 1987; 69: 22-6.
    PubMedGoogle Scholar
  • 31 Nauland U, Rijken DC. Activation of thrombin-inactivated single-chain urokinase-type plasminogen activator by dipeptidyl peptidase I. Eur J Biochem 1994; 223: 497-501.
    CrossrefPubMedGoogle Scholar
  • 32 Powell-Jones CHJ. Rapid SDS-PAGE zymography of plasminogen activators. Thromb Res 1988; 49: 299-302.
    CrossrefPubMedGoogle Scholar
  • 33 Medcalf RL, Van der Berg E, Schleuning WD. Glucocorticoid modulated gene expression of tissue and urinary type plasminogen activator and plasminogen activator inhibitor 1 and 2. J Cell Biol 1988; 106: 971-8.
    CrossrefPubMedGoogle Scholar
  • 34 Cox KH, de Leon DV, Angerer LM, Angerer RC. Detection of mRNAs in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Dev Biol 1984; 101: 485-502.
    CrossrefPubMedGoogle Scholar
  • 35 Wilcox JN, Smith KM, Williams LT, Schwartz SM, Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest 1988; 82: 1134-43.
    CrossrefPubMedGoogle Scholar
  • 36 Höltke HJ, Kessler C. Non-radioactive labeling of RNA transcripts in vitro with the hapten digoxigenin (DIG); hybridization and ELISA based detection. Nucl Acid Res 1990; 18: 5843-51.
    CrossrefPubMedGoogle Scholar
  • 37 Bankfalvi A, Navabi H, Bier B, Böcker W, Jasani B, Schmid KW. Wet autoclave pretreatment for antigen retrieval in diagnostic immunohistochemistry. J Pathol 1994; 174: 223-8.
    CrossrefPubMedGoogle Scholar
  • 38 Siegel S, Castellan JN. Nonparametric statistics for the behavioral sciences. Singapore: McGraw-Hill Book Co.; 1988: 190-223.
    Google Scholar
  • 39 Besser D, Verde P, Nagamine Y, Blasi F. Signal transduction and the UPA/UPAR system. Fibrinolysis 1996; 10: 215-37.
    PubMedGoogle Scholar
  • 40 Robbie LA, Booth NA, Brown PAJ, Bennett B. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1996; 16: 539-45.
    CrossrefPubMedGoogle Scholar
  • 41 Falkenberg M, Tjärnström J, Örtenwall P, Olausson M, Risberg B. Localization of fibrinolytic activators and inhibitors in normal and atherosclerotic vessels. Thromb Haemost 1996; 75: 933-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Conese M, Blasi F. Urokinase/urokinase receptor system: internalization/ degradation of urokinase-serpin complexes: mechanism and regulation. Biol Chem Hoppe-Seyler 1995; 376: 143-55.
    PubMedGoogle Scholar
  • 43 Wilhelm S, Wilhelm O, Schmitt M, Graeff H. Inactivation of receptor-bound pro-urokinase-type plasminogen activator (pro-uPA) by thrombin and thrombin/ thrombomodulin complex. Biol Chem Hoppe-Seyler 1994; 375: 603-8.
    PubMedGoogle Scholar
  • 44 Dechend R, Mo X, Schulz W, Gross M, Praus M, Dietz R. Thrombin receptor and urokinase-type plasminogen activator are colocalized in vascular smooth muscle cells derived from human carotid atherosclerotic plaques. Fibrinolysis 1996; 10: 41-5.
    PubMedGoogle Scholar
  • 45 Padró T, Steins M, Hammel D, Kienast J. Atherosclerosis-related alterations of the plasminogen activator/plasmin system in vascular wall: studies in human coronary arteries. Thromb Haemost 1993; 69: 971 (Abstract).
    PubMedGoogle Scholar
  • 46 Grondahl-Hansen J, Kirkeby LT, Ralfkiaer E, Kristensen P, Lund LR, Dano K. Urokinase-type plasminogen activator in endothelial cells during acute inflammation of the appendix. Am J Pathol 1989; 135: 631-6.
    PubMedGoogle Scholar
  • 47 Bacharach E, Itin A, Keshet E. In vivo patterns of expression of urokinase and its inhibitor PAI-1 suggest a concerted role in regulating physiological angiogenesis. Proc Natl Acad Sci USA 1992; 89: 10686-90.
    CrossrefPubMedGoogle Scholar
  • 48 Dollery CM, McEwan J, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995; 77: 863-8.
    CrossrefPubMedGoogle Scholar
  • 49 Fuster V, Badimón L, Badimón JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (part one). N Engl J Med 1992; 326: 242-50.
    CrossrefPubMedGoogle Scholar
  • 50 Fuster V, Badimón L, Badimón JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (part two). N Engl J Med 1992; 326: 310-8.
    CrossrefPubMedGoogle Scholar
  • 51 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and athero-thrombosis. Thromb Haemost 1993; 70: 138-43.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
    PubMedGoogle Scholar
  • 53 Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulins characterizes a risk group among survivors of acute myocar-dial infarction. Thromb Haemost 1987; 57: 137-9.
    Article in Thieme ConnectPubMedGoogle Scholar