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Thromb Haemost 2001; 86(05): 1305-1313
DOI: 10.1055/s-0037-1616066
Review Article
Schattauer GmbH

Attenuation by Fibrates of Plasminogen Activator Inhibitor Type-1 Expression in Human Arterial Smooth Muscle Cells

Thomas K. Nordt
1   Department of Cardiology, University of Freiburg, Germany
,
Steffen Lutzi
2   Department of Cardiology, Germany
,
Johannes Ruef
2   Department of Cardiology, Germany
,
Karlheinz Peter
1   Department of Cardiology, University of Freiburg, Germany
,
Ernst Klar
3   Department of Surgery, University of Heidelberg, Germany
,
Wolfgang Kübler
2   Department of Cardiology, Germany
,
Burton E. Sobel
4   Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
,
Christoph Bode
1   Department of Cardiology, University of Freiburg, Germany
› Author AffiliationsThis work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (DFG No214/2-1), by a grant-in-aid from the Medizinische Fakultät Heidelberg (148/95), and by a grant from the latter (178/97). The authors thank Stephanie Riester and Sandra Ernst for excellent technical assistance.
Further Information

Publication History

Received 01 March 2001

Accepted after resubmission 18 July 2001

Publication Date:
13 December 2017 (online)

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Summary

Human atherosclerotic lesions exhibit increased expression of plasminogen activator inhibitor type-1 (PAI-1) that has been implicated in atherogenesis. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells.

Human aortic smooth muscle cells were exposed to selected growth factors. PAI-1 expression was stimulated most powerfully by TGF-β (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23% (p = ns) and TGF-β -induced PAI-1 expression by 52% (p = 0.017) whereas t-PA and total protein synthesis was not affected. Changes in PAI-1 protein accumulation reflected PAI-1 gene expression attributable to modulation of half-life of PAI-1 mRNA by gemfibrozil. Inhibition by other fibrates was less.

Gemfibrozil specifically attenuates TGF-β -induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for normalizing increased PAI-1 expression in arterial walls in patients in whom PAI-1 expression is increased.

Keywords

Arteriosclerosis - fibrates - growth factors - smooth muscle cells - endogenous fibrinolysis
 

  • References

  • 1 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457-62.
    CrossrefPubMedGoogle Scholar
  • 2 Hamsten A. The hemostatic system and coronary heart disease. Thromb Res 1993; 70: 1-38.
    CrossrefPubMedGoogle Scholar
  • 3 Nordt TK, Peter K, Ruef J, Kübler W, Bode C. Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease. Thromb Haemost 1999; 82 suppl 14-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Sobel BE. ncreased plasminogen activator inhibitor-1 and vasculopathy: A reconcilable paradox. Circulation 1999; 99: 2496-8.
    CrossrefPubMedGoogle Scholar
  • 5 Sobel BE. Coronary artery disease and fibrinolysis: From the blood to the vessel wall. Thromb Haemost 1999; 82: 8-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Schneider DJ, Absher PM, Russell JC, Sobel BE. Fibrinolysis and atherogenesis in the JCR: LA-cp rat in relation to insulin and triglyceride concentrations in blood. Diabetologia 1997; 41: 141-7.
    PubMedGoogle Scholar
  • 7 Thögersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women. Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
    CrossrefPubMedGoogle Scholar
  • 8 Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89: 6998-7002.
    CrossrefPubMedGoogle Scholar
  • 9 Lupu F, Bergonzelli GE, Heim DA, Cousin E, Genton CY, Bachmann F, Kruithof EKO. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13: 1090-100.
    CrossrefPubMedGoogle Scholar
  • 10 Chomiki N, Henry M, Alessi MC, Anfosso F, Juhan-Vague I. Plasminogen activator inhibitor-1 expression in human liver and healthy or atherosclerotic vessel walls. Thromb Haemost 1994; 72: 44-53.
    PubMedGoogle Scholar
  • 11 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
  • 12 Padró T, Steins M, Li CX, Mesters RM, Hammel D, Scheld HH, Kienast J. Comparative analysis of plasminogen activator inhibitor-1 expression in different types of atherosclerotic lesions in coronary arteries from human heart explants. Cardiovasc Res 1997; 36: 28-36.
    CrossrefPubMedGoogle Scholar
  • 13 Schneider DJ, Ricci MA, Taatjes DJ, Baumann PQ, Reese JC, Leavitt BJ, Absher PM, Sobel BE. Changes in arterial expression of fibrinolytic system proteins in atherogenesis. Arterioscler Thromb Vasc Biol 1997; 17: 3294-301.
    CrossrefPubMedGoogle Scholar
  • 14 Nordt TK, Sawa H, Fujii S, Bode C, Sobel BE. Augmentation of arterial endothelial cell expression of the plasminogen activator inhibitor type-1 (PAI-1) gene by proinsulin and insulin in vivo. J Mol Cell Cardiol 1998; 30: 1535-43.
    CrossrefPubMedGoogle Scholar
  • 15 Reilly CF, McFall RC. Platelet-derived growth factor and transforming growth factor- regulate plasminogen activator inhibitor-1 synthesis in vascular smooth muscle cells. J Biol Chem 1991; 266: 9419-27.
    PubMedGoogle Scholar
  • 16 Bochaton-Piallat ML, Gabbiani G, Pepper MS. Plasminogen activator expression in rat arterial smooth muscle cells depends on their phenotype and is modulated by cytokines. Circ Res 1998; 82: 1086-93.
    CrossrefPubMedGoogle Scholar
  • 17 Lee L, Vaughan DE, Parikh SH, Grodzinsky AJ, Libby P, Lark MW, Lee RT. Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells. Circ Res 1996; 78: 44-9.
    CrossrefPubMedGoogle Scholar
  • 18 Sperti G, van Leeuwen R, Maseri A, Kluft C. Platelet-derived growth factor increases plasminogen activator inhibitor-1 activity and mRNA in rat cultured vascular smooth muscle. Ann N Y Acad Sci 1992; 667: 167-80.
    PubMedGoogle Scholar
  • 19 Cockell KA, Ren S, Sun J, Angel A, Shen GX. Effect of thrombin on release of plasminogen activator inhibitor-1 from cultured primate arterial smooth muscle cells. Thromb Res 1995; 77: 119-31.
    CrossrefPubMedGoogle Scholar
  • 20 Wojta J, Gallicchio M, Zoellner H, Hufnagl P, Last K, Filonzi EL, Binder BR, Hamilton JA, McGrath K. Thrombin stimulates expression of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in cultured human vascular smooth muscle cells. Thromb Haemost 1993; 70: 469-74.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Noda-Heiny H, Fujii S, Sobel BE. Induction of vascular smooth muscle cell expression of plasminogen activator inhibitor-1 by thrombin. Circ Res 1993; 72: 36-43.
    CrossrefPubMedGoogle Scholar
  • 22 Wang W, Chen HJ, Schwartz A, Cannon PJ, Rabbani LE. T cell lymphokines modulate bFGF-induced smooth muscle cell fibrinolysis and migration. Am J Physiol 1997; 272: C392-C398.
    CrossrefPubMedGoogle Scholar
  • 23 Louwrens HD, Kwaan HC, Pearce WH, Yao JST, Verrusio E. Plasminogen activator and plasminogen activator inhibitor expression by normal and aneurysmal human aortic smooth muscle cells in culture. Eur J Endovasc Surg 1995; 10: 289-93.
    CrossrefPubMedGoogle Scholar
  • 24 Fujii S, Sobel BE. Direct effects of gemfibrozil on the fibrinolytic system. Diminution of synthesis of plasminogen activator inhibitor type 1. Circulation 1992; 85: 1888-93.
    CrossrefPubMedGoogle Scholar
  • 25 Nordt TK, Kornas K, Peter K, Fujii S, Sobel BE, Kübler W, Bode C. Attenuation by gemfibrozil of expression of plasminogen activator inhibitor type-1 induced by insulin and its precursors. Circulation 1997; 95: 677-83.
    CrossrefPubMedGoogle Scholar
  • 26 Arts J, Kockx M, Princen HMG, Kooistra T. Studies on the mechanism of fibrate-inhibited expression of plasminogen activator inhibitor-1 in cultured hepatocytes from cynomolgus monkey. Arterioscler Thromb Vasc Biol 1997; 17: 26-32.
    CrossrefPubMedGoogle Scholar
  • 27 Kockx M, Princen HMG, Kooistra T. Fibrate-modulated expression of fibrinogen, plasminogen activator inhibitor-1 and apolipoprotein A-I in cultured cynomolgus monkey hepatocytes. Role of the peroxisome proliferator-activated receptor-α. Thromb Haemost 1998; 80: 942-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Fujii S, Sawa H, Sobel BE. Inhibition of endothelial cell expression of plasminogen activator inhibitor type-1 by gemfibrozil. Thromb Haemost 1993; 70: 642-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Nilsson L, Takemura T, Eriksson P, Hamsten A. Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells. Arterioscler Thromb Vasc Biol 1999; 19: 1577-81.
    CrossrefPubMedGoogle Scholar
  • 30 Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanisms of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98: 2088-93.
    CrossrefPubMedGoogle Scholar
  • 31 Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237-45.
    CrossrefPubMedGoogle Scholar
  • 32 Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341: 410-8.
    CrossrefPubMedGoogle Scholar
  • 33 Hall FL, Benya PD, Padilla SR, Carbonaro-Hall D, Williams R, Buckley S, Warburton D. Transforming growth factor- type-II receptor signalling: intrinsic/associated casein kinase activity, receptor interaction and functional effects of blocking antibodies. Biochem J 1996; 316: 303-10.
    CrossrefPubMedGoogle Scholar
  • 34 Todd PA, Ward A. Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidemia. Drugs 1988; 36: 314-39.
    CrossrefPubMedGoogle Scholar
  • 35 Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients. A potential factor predisposing to thrombosis and its persistence. Circulation 1998; 97: 2213-21.
    CrossrefPubMedGoogle Scholar
  • 36 Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosen-field RL, Polonsky KS. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 2108-16.
    PubMedGoogle Scholar