Plasminogen Activator Inhibitor Type-1 (PAI-1) and its Role in Cardiovascular Disease

Thomas K. Nordt; Karlheinz Peter; Johannes Ruef; Wolfgang Kübler; Christoph Bode

doi:10.1055/s-0037-1615546

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(S 01): 14-18
DOI: 10.1055/s-0037-1615546

Commentaries

Schattauer GmbH

Plasminogen Activator Inhibitor Type-1 (PAI-1) and its Role in Cardiovascular Disease

Authors

Thomas K. Nordt

¹Abteilung Kardiologie, Medizinische Klinik und Poliklinik, Universität Freiburg
Karlheinz Peter

¹Abteilung Kardiologie, Medizinische Klinik und Poliklinik, Universität Freiburg
Johannes Ruef

²Abteilung Kardiologie, Medizinische Klinik und Poliklinik, Universität Heidelberg, Germany
Wolfgang Kübler

²Abteilung Kardiologie, Medizinische Klinik und Poliklinik, Universität Heidelberg, Germany
Christoph Bode

¹Abteilung Kardiologie, Medizinische Klinik und Poliklinik, Universität Freiburg

Abstract

Summary

Cardiovascular disease is responsible for approximately 50% of total mortality in Europe, the USA and Japan (1). Established risk factors including smoking, hypercholesterolemia, and hypertension explain about half of the incidence of cardiovascular disease only (2). Reduced endogenous fibrinolytic activity secondary to increased plasma activity of plasminogen activator inhibitor type-1 (PAI-1) is now considered as a new cardiovascular risk factor. In this review, evidence is gathered for the notion that PAI-1 constitutes a predictor of cardiovascular disease and also contributes to the development of cardiovascular disease as a pathogenetic factor. The review will focus on experimental studies modulating PAI-1 activity and clinical studies addressing coronary heart disease, myocardial infarction, restenosis after coronary angioplasty, and graft occlusion after coronary artery bypass grafting.

Key words

Endogenous fibrinolysis - atherogenesis - arteriosclerosis - risk factor

Full Text

References

References
1 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
2 Koenig W. Haemostatic risk factors for cardiovascular diseases. Eur Heart J 1998; 19 (suppl C) C39-43.
3 Nordt TK, Peter K, Kubler W, Bode C. Regulation of the synthesis of plasminogen activator inhibitor type 1 (PAI-1): pathogenetic mechanism of atherosclerosis in diabetes mellitus?. Fibrinolysis Proteolysis 1997; 11 (suppl 2) 141-7.
4 Krishnamurti C, Barr CF, Hassett MA, Young GD, Alving BM. Plasminogen activator inhibitor: A regulator of ancrod-induced fibrin deposition in rabbits. Blood 1987; 69: 798-803.
5 Krishnamurti C, Bolan C, Colleton CA, Reilly TM, Alving BM. Role of plasminogen activator inhibitor-1 in promoting fibrin deposition in rabbits infused with ancrod or thrombin. Blood 1993; 82: 3631-6.
6 Vaughan DE, Declerck PJ, van Houtte E, de Mol M, Collen D. Reactivated recombinant plasminogen activator inhibitor-1 (rPAI-1) effectively prevents thrombolysis in vivo. Thromb Haemost 1992; 68: 60-3.
7 Reilly CF, Fujita T, Hutzelmann JE, Mayer EJ, Shebuski RJ. Plasminogen activator inhibitor-1 suppresses endogenous fibrinolysis in a canine model of pulmonary embolism. Circulation 1991; 84: 287-92.
8 Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 1990; 346: 74-6.
9 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.
10 Levi M, Biemond BJ, van Zonneveld AJ, ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibiton of thrombus extension in models of experimental thrombosis. Circulation 1992; 85: 305-12.
11 Biemond BJ, Levi M, Coronel R, Janse MJ, ten Cate JW, Pannekoek H. Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis. Effects of a plasminogen activator inhibitor type 1-neutralizing monoclonal antibody. Circulation 1995; 91: 1175-81.
12 Berry CN, Lunven C, Lechaire I, Girardot C, O'Connor SE. Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis. British Journal of Pharmacology 1998; 125: 29-34.
13 Carmeliet P, Kieckens L, Schoonjans L, van Ream B, Nuffelen AV, Prendergast G, Cole M, Bronson R, Collen D, Mulligan RC. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 1993; 92: 2746-55.
14 Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den, Oord JJ, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on Hemostasis, thrombosis, and thrombolysis. J Clin Invest 1993; 92: 2756-60.
15 Schleef RR, Higgins DL, Pillemer E, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest 1989; 83: 1747-52.
16 Dieval J, Nguyen G, Gross S, Delobel J, Kruithof EKO. A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1. Blood 1991; 77: 528-32.
17 Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D. Complete deficiency of plasminogen activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 1992; 327: 1729-33.
18 Lee MH, Vosburgh E, Anderson K, McDonagh J. Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. Blood 1993; 81: 2357-62.
19 Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor-1 (PAI-1) deficiency: Characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 1997; 90: 204-8.
20 Francis Jr. RB, Liebman H, Koehler S, Feinstein DI. Accelerated fibrinolysis in amyloidosis: specific binding of tissue plasminogen activator inhibitor by an amyloidogenic monoclonal IgG. Blood 1986; 68 (suppl 1) 333 (abstr.)
21 Charlton PA, Faint RW, Bent F, Bryans J, Chicarelli-Robinson I, Mackie I, Machin S, Bevan P. Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity. Thromb Haemost 1996; 75: 808-15.
22 Charlton P, Faint R, Barnes C, Bent F, Folkes A, Templeton D, Mackie I, Machin S, Bevan P. XR5118, a novel modulator of plasminogen activator inhibitor-1 (PAI-1), increases endogenous tPA activity in the rat. Fibrinolysis Proteolysis 1997; 11: 51-6.
23 Vinogradsky B, Bell SP, Woodcock-Mitchell J, Ohtani A, Fujii S. A new butadiene derivative, T-686, inhibits plasminogen activator inhibitor type-1 production in vitro by cultured human vascular endothelial cells and development of atherosclerotic lesions in vivo in rabbits. Thromb Res 1997; 85: 305-14.
24 Rocha E, Paramo JA. The relationship between impaired fibrinolysis and coronary heart disease: a role for PAI-1. Fibrinolysis 1994; 8: 294-303.
25 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
26 Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, Juhan-Vague I. Clearance of tissue plasminogen activator (tPA) and tPA/plasminogen activator inhibitor type 1 (PAI-1) complex. Relationship to elevated tPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.
27 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors and long-term incidence of ischemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
28 Lowe GDO, Yarnell JWG, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-33.
29 Munkvad S, Gram J, Jespersen J. A depression of active tissue plasminogen activator in plasma characterizes patients with unstable angina pectoris who develop myocardial infarction. Eur Heart J 1990; 11: 525-8.
30 Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up. Circulation 1993; 88: 2030-4.
31 Nilsson TK. Analysis of factors affecting tissue plasminogen activator and antigen concentration before and after venous occlusion in 123 patients. Clin Chem Enzymol Commun 1989; 1: 335-41.
32 Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 1997; 78: 656-60.
33 Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espaiia F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 1988; 59: 535-41.
34 Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J 1991; 12: 157-61.
35 Jansson JH, Norberg B, Nilsson TK. Impact of acute phase on concentrations of tissue plasminogen activator and plasminogen activator inhibitor in plasma after deep-vein thrombosis or open-heart surgery. Clin Chem 1989; 35: 1544-5.
36 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. for the PLAT Group. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. Arterioscler Thromb 1993; 13: 1412-7.
37 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
38 Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. on behalf of the ECAT Study Group. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-63.
39 Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
40 Chmielewska J, Ranby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-36.
41 Wiman B, Chmielewska J, Ranby M. Inactivation of tissue plasminogen activator in plasma: demonstration of a complex with a new rapid inhibitor. J Biol Chem 1984; 259: 3644-7.
42 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction. Lancet 1987; II: 3-9.
43 Gram J, Jespersen J, Kluft C, Rijken DC. On the usefulness of fibrinolysis variables in the characterization of a risk group for myocardial reinfarction. Acta Med Scand 1987; 221: 149-53.
44 Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulins characterises a risk group among survivors of acute myocardial infarction. Thromb Haemost 1987; 57: 137-9.
45 Gray RP, Yudkin JS, Patterson DL. Plasminogen activator inhibitor: a risk factor for myocardial infarction in diabetic patients. B Heart J 1993; 69: 228-32.
46 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.
47 Padro 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.
48 Kirschstein W, Simianer S, Dempfle CE, Keller H, Stegaru B, Rentrop P, Heene DL. Impaired fibrinolytic capacity and tissue plasminogen activator release in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). Thromb Haemost 1989; 62: 772-5.
49 Huber K, Jorg M, Probst P, Schuster E, Lang I, Kaindl F, Binder BR. A decrease in plasminogen activator inhibitor-1 activity after successful percutaneous transluminal coronary angioplasty is associated with a significantly reduced risk for coronary restenosis. Thromb Haemost 1992; 67: 209-13.
50 Sakata K, Miura F, Sugino H, Shinobe M, Shirotani M, Yoshida H, Mori N, Hoshino T, Takada A. Impaired fibrinolysis early after percutaneous transluminal coronary angioplasty is associated with restenosis. Am Heart J 1996; 131: 1-6.
51 Ishiwata S, Tukada T, Nakanishi S, Nishiyama S, Seki A. Postangioplasty restenosis: Platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis. Am Heart J 1997; 133: 387-92.
52 Aronson D, Bloomgarden Z, Rayfield EJ. Potential mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol 1996; 27: 528-35.
53 Weintraub WS, Ghazzal ZMB, Douglas Jr. JS, Liberman H, Morris DC, Cohen CL, King III SB. Initial management and long-term clinical outcome of restenosis after initially successful percutaneous transluminal coronary angioplasty. Am J Cardiol 1992; 70: 47-55.
54 Sobel BE. Potentiation of vasculopathy by insulin. Implications from an NHLBI clinical alert. Circulation 1996; 93: 1613-15.
55 Califf RM, Fortin DF, Frid DJ, Harlan III WR, Ohman EM, Bengtson JR, Nelson CL, Tcheng JE, Mark DB, Stack RS. Restenosis after coronary angioplasty: An overview. J Am Coll Cardiol 1991; 17: 2B-13B.
56 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resitance and atherothrombosis. Diabetologia 1991; 34: 457-62.
57 Moor E, Hamsten A, Blomback M, Herzfeld I, Wiman B, Ryden L. Haemostatic factors and inhibitors and coronary artery bypass grafting: preoperative alterations and relations to graft occlusion. Thromb Haemost 1994; 72: 335-42.
58 Rifón J, Páramo JA, Panizo C, Montes R, Rocha E. The increase of plasminogen activator inhibitor activity is associated with graft occlusion in patients undergoing aorto-coronary bypass surgery. Br J Haematol 1997; 99: 262-7.