Plasminogen Activator Inhibitor-1 in Aging

Koji Yamamoto; Kyosuke Takeshita; Hidehiko Saito

doi:10.1055/s-0034-1384635

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2014; 40(06): 652-659
DOI: 10.1055/s-0034-1384635

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Plasminogen Activator Inhibitor-1 in Aging

Authors

Koji Yamamoto

¹Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan
Kyosuke Takeshita

²Department of Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
Hidehiko Saito

³Nagoya Medical Center, Nagoya, Japan

Abstract

Plasminogen activator inhibitor-1 (PAI-1), a principal inhibitor of fibrinolysis, is induced in thrombotic, fibrotic, and cardiovascular diseases, which in turn primarily afflict the older population. This induction of PAI-1 may play an important role in the pathology of these diseases as PAI-1 can regulate the dissolution of fibrin and also inhibit the degradation of the extracellular matrix by reducing plasmin generation. PAI-1 expression is elevated in aged individuals and is significantly upregulated in a variety of pathologies associated with the process of aging, including myocardial and cerebral infarction, vascular (athero) sclerosis, cardiac and lung fibrosis, metabolic syndromes (e.g., hypertension, hyperlipidemia, and insulin resistance), cancer, and inflammatory/stress responses. Thus, PAI-1 may play a critical role in the development of aging-associated pathological changes. In addition, PAI-1 is recognized as a marker of senescence and a key member of a group of proteins collectively known as the senescence-messaging secretome. In this review, we highlight the role of PAI-1 in the pathophysiology of aging and aging-associated disorders.

Keywords

PAI-1 - thrombosis - fibrosis - vascular sclerosis - metabolic syndrome

Full Text

References

References
1 Tracy RP, Bovill EG. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med 1992; 116 (12) 1307-1312
2 Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002; 28 (6) 555-568
3 Kiechl S, Willeit J ; Bruneck Study Group. The natural course of atherosclerosis. Part II: vascular remodeling. Arterioscler Thromb Vasc Biol 1999; 19 (6) 1491-1498
4 Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms—the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994; 71 (6) 719-722
5 Abbate R, Prisco D, Rostagno C, Boddi M, Gensini GF. Age-related changes in the hemostatic system. Int J Clin Lab Res 1993; 23 (1) 1-3
6 Hashimoto Y, Kobayashi A, Yamazaki N, Sugawara Y, Takada Y, Takada A. Relationship between age and plasma t-PA, PA-inhibitor, and PA activity. Thromb Res 1987; 46 (5) 625-633
7 Loskutoff DJ, Sawdey M, Mimuro J. Type 1 plasminogen activator inhibitor. In: Coller B, , ed. Progress in Hemostasis and Thrombosis. Philadelphia, PA: WB Saunders Company; 1988: 87-115
8 Yamamoto K, Saito H. A pathological role of increased expression of plasminogen activator inhibitor-1 in human or animal disorders. Int J Hematol 1998; 68 (4) 371-385
9 Yamamoto K, Takeshita K, Kojima T, Takamatsu J, Saito H. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 2005; 66: 276-285
10 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383 (6599) 441-443
11 Heymans S, Luttun A, Nuyens D , et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 1999; 5 (10) 1135-1142
12 Eren M, Gleaves LA, Atkinson JB, King LE, Declerck PJ, Vaughan DE. Reactive site-dependent phenotypic alterations in plasminogen activator inhibitor-1 transgenic mice. J Thromb Haemost 2007; 5 (7) 1500-1508
13 Loskutoff DJ. Regulation of PAI-1 gene expression. Fibrinolysis 1991; 5: 197-206
14 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-α, and transforming growth factor-β. J Clin Invest 1991; 88 (4) 1346-1353
15 Yamamoto K, Loskutoff DJ. Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator. J Clin Invest 1996; 97 (11) 2440-2451
16 Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor- α and lipopolysaccharide. J Clin Invest 1996; 97 (1) 37-46
17 Yamamoto K, Takeshita K, Shimokawa T , et al. Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A 2002; 99 (2) 890-895
18 Takeshita K, Hayashi M, Iino S , et al. Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction. Am J Pathol 2004; 164 (2) 449-456
19 Naito M, Funaki C, Hayashi T , et al. Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultured vascular smooth muscle cells. Atherosclerosis 1992; 96 (2-3) 227-234
20 Smith EB, Cochran S. Factors influencing the accumulation in fibrous plaques of lipid derived from low density lipoprotein. II. Preferential immobilization of lipoprotein (a) (Lp(a)). Atherosclerosis 1990; 84 (2-3) 173-181
21 Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96 (13) 4212-4215
22 Arenillas JF, Alvarez-Sabín J, Molina CA , et al. Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis. Stroke 2008; 39 (5) 1456-1463
23 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 (7) 457-462
24 Schneiderman J, Sawdey MS, Keeton MR , et al. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A 1992; 89 (15) 6998-7002
25 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 (1) 44-53
26 Cristofalo VJ, Pignolo RJ. Molecular markers of senescence in fibroblast-like cultures. Exp Gerontol 1996; 31 (1-2) 111-123
27 Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8 (9) 729-740
28 Rerolle JP, Hertig A, Nguyen G, Sraer JD, Rondeau EP. Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney Int 2000; 58 (5) 1841-1850
29 Oikawa T, Freeman M, Lo W, Vaughan DE, Fogo A. Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. Kidney Int 1997; 51 (1) 164-172
30 Yamamoto K, Loskutoff DJ. The kidneys of mice with autoimmune disease acquire a hypofibrinolytic/procoagulant state that correlates with the development of glomerulonephritis and tissue microthrombosis. Am J Pathol 1997; 151 (3) 725-734
31 Zaman AK, Fujii S, Sawa H , et al. Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic mice. Circulation 2001; 103 (25) 3123-3128
32 Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE. Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation 2001; 104 (7) 839-844
33 Blasi F, Vassalli JD, Danø K. Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors. J Cell Biol 1987; 104 (4) 801-804
34 Olman MA, Mackman N, Gladson CL, Moser KM, Loskutoff DJ. Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. J Clin Invest 1995; 96 (3) 1621-1630
35 Eitzman DT, McCoy RD, Zheng X , et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996; 97 (1) 232-237
36 Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995; 95 (3) 995-1001
37 Koh KK, Ahn JY, Han SH , et al. Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 2003; 42 (5) 905-910
38 Okada H, Watanabe Y, Kikuta T , et al. Bradykinin decreases plasminogen activator inhibitor-1 expression and facilitates matrix degradation in the renal tubulointerstitium under angiotensin-converting enzyme blockade. J Am Soc Nephrol 2004; 15 (9) 2404-2413
39 Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998; 32 (6) 965-971
40 Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS. eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ Res 2001; 89 (9) 793-798
41 Hayashi T, Matsui-Hirai H, Miyazaki-Akita A , et al. Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. Proc Natl Acad Sci U S A 2006; 103 (45) 17018-17023
42 Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system. Arterioscler Thromb Vasc Biol 1998; 18 (11) 1771-1779
43 Katoh M, Egashira K, Mitsui T, Chishima S, Takeshita A, Narita H. Angiotensin-converting enzyme inhibitor prevents plasminogen activator inhibitor-1 expression in a rat model with cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis. J Mol Cell Cardiol 2000; 32 (1) 73-83
44 Weisberg AD, Albornoz F, Griffin JP , et al. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodeling. Arterioscler Thromb Vasc Biol 2005; 25 (2) 365-371
45 Boe AE, Eren M, Murphy SB , et al. Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation 2013; 128 (21) 2318-2324
46 Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94 (9) 2057-2063
47 Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313 (25) 1557-1563
48 Hamsten A, de Faire U, Walldius G , et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2 (8549) 3-9
49 Collet JP, Montalescot G, Vicaut E , et al. Acute release of plasminogen activator inhibitor-1 in ST-segment elevation myocardial infarction predicts mortality. Circulation 2003; 108 (4) 391-394
50 Iacoviello L, Agnoli C, De Curtis A , et al. Type 1 plasminogen activator inhibitor as a common risk factor for cancer and ischaemic vascular disease: the EPICOR study. BMJ Open 2013; 3 (11) e003725
51 Eriksson P, Kallin B, van 't Hooft FM, Båvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995; 92 (6) 1851-1855
52 Hultman K, Björklund U, Hansson E, Jern C. Potentiating effect of endothelial cells on astrocytic plasminogen activator inhibitor type-1 gene expression in an in vitro model of the blood-brain barrier. Neuroscience 2010; 166 (2) 408-415
53 Nagai N, Suzuki Y, Van Hoef B, Lijnen HR, Collen D. Effects of plasminogen activator inhibitor-1 on ischemic brain injury in permanent and thrombotic middle cerebral artery occlusion models in mice. J Thromb Haemost 2005; 3 (7) 1379-1384
54 Tjärnlund-Wolf A, Brogren H, Lo EH, Wang X. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke 2012; 43 (10) 2833-2839
55 Dohgu S, Takata F, Matsumoto J , et al. Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1. Microvasc Res 2011; 81 (1) 103-107
56 Soeda S, Koyanagi S, Kuramoto Y , et al. Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system. Thromb Haemost 2008; 100 (6) 1014-1020
57 McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994; 43 (1) 104-109
58 Vague P, Juhan-Vague I, Aillaud MF , et al. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism 1986; 35 (3) 250-253
59 Brouwers MC, Govers-Riemslag J, Schalkwijk CG , et al. Plasma PAI-1 levels are independently related to fatty liver and hypertriglyceridemia in familial combined hyperlipidemia, involvement of apolipoprotein E. Thromb Res 2008; 122 (4) 466-472
60 Shimomura I, Funahashi T, Takahashi M , et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 2 (7) 800-803
61 Festa A, D'Agostino Jr R, Tracy RP, Haffner SM ; Insulin Resistance Atherosclerosis Study. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002; 51 (4) 1131-1137
62 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 1996; 2 (5) 568-582
63 Ma LJ, Mao SL, Taylor KL , et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 2004; 53 (2) 336-346
64 Gabriely I, Yang XM, Cases JA, Ma XH, Rossetti L, Barzilai N. Hyperglycemia induces PAI-1 gene expression in adipose tissue by activation of the hexosamine biosynthetic pathway. Atherosclerosis 2002; 160 (1) 115-122
65 Samad F, Pandey M, Bell PA, Loskutoff DJ. Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes. Mol Med 2000; 6 (8) 680-692
66 Sobel BE, Hardison RM, Genuth S , et al; BARI 2D Investigators. Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation 2011; 124 (6) 695-703
67 Nishimura S, Manabe I, Nagai R. Adipose tissue inflammation in obesity and metabolic syndrome. Discov Med 2009; 8 (41) 55-60
68 Uchida Y, Takeshita K, Yamamoto K , et al. Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1. Diabetes 2012; 61 (6) 1552-1561
69 Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 1995; 95 (5) 2409-2415
70 Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil GS, Loskutoff DJ. Tumor necrosis factor α is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci U S A 1999; 96 (12) 6902-6907
71 Samad F, Yamamoto K, Pandey M, Loskutoff DJ. Elevated expression of transforming growth factor-β in adipose tissue from obese mice. Mol Med 1997; 3 (1) 37-48
72 Pralong G, Calandra T, Glauser M-P , et al. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61 (3) 459-462
73 Green J, Doughty L, Kaplan SS, Sasser H, Carcillo JA. The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure. Thromb Haemost 2002; 87 (2) 218-223
74 Emeis JJ, Brouwer A, Barelds RJ, Horan MA, Durham SK, Kooistra T. On the fibrinolytic system in aged rats, and its reactivity to endotoxin and cytokines. Thromb Haemost 1992; 67 (6) 697-701
75 Yamamoto K, Shimokawa T, Yi H , et al. Aging accelerates endotoxin-induced thrombosis : increased responses of plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging. Am J Pathol 2002; 161 (5) 1805-1814
76 Rosas GO, Zieman SJ, Donabedian M, Vandegaer K, Hare JM. Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. J Mol Cell Cardiol 2001; 33 (10) 1849-1859
77 Newland JR, Haire WD. Elevated plasminogen activator inhibitor levels found in patients with malignant conditions. Am J Clin Pathol 1991; 96 (5) 602-604
78 Prendergast GC, Diamond LE, Dahl D, Cole MD. The c-myc-regulated gene mrl encodes plasminogen activator inhibitor 1. Mol Cell Biol 1990; 10 (3) 1265-1269
79 Boccaccio C, Sabatino G, Medico E , et al. The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 2005; 434 (7031) 396-400
80 Kristensen P, Pyke C, Lund LR, Andreasen PA, Danø K. Plasminogen activator inhibitor-type 1 in Lewis lung carcinoma. Histochemistry 1990; 93 (6) 559-566
81 Pyke C, Kristensen P, Ralfkiaer E, Eriksen J, Danø K. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma. Cancer Res 1991; 51 (15) 4067-4071
82 Pedersen H, Brünner N, Francis D , et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54 (17) 4671-4675
83 Nekarda H, Schmitt M, Ulm K , et al. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res 1994; 54 (11) 2900-2907
84 Kuhn W, Schmalfeldt B, Reuning U , et al. Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc. Br J Cancer 1999; 79 (11-12) 1746-1751
85 Kobayashi H, Fujishiro S, Terao T. Impact of urokinase-type plasminogen activator and its inhibitor type 1 on prognosis in cervical cancer of the uterus. Cancer Res 1994; 54 (24) 6539-6548
86 Danø K, Andreasen PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 1985; 44: 139-266
87 Bajou K, Noël A, Gerard RD , et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4 (8) 923-928
88 Bajou K, Masson V, Gerard RD , et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 2001; 152 (4) 777-784
89 Rosengren A, Hawken S, Ôunpuu S , et al; INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364 (9438) 953-962
90 Räikkönen K, Lassila R, Keltikangas-Järvinen L, Hautanen A. Association of chronic stress with plasminogen activator inhibitor-1 in healthy middle-aged men. Arterioscler Thromb Vasc Biol 1996; 16 (3) 363-367
91 Supiano MA, Hogikyan RV, Sidani MA, Galecki AT, Krueger JL. Sympathetic nervous system activity and alpha-adrenergic responsiveness in older hypertensive humans. Am J Physiol 1999; 276 (3 Pt 1) E519-E528
92 Larsson PT, Wiman B, Olsson G, Angelin B, Hjemdahl P. Influence of metoprolol treatment on sympatho-adrenal activation of fibrinolysis. Thromb Haemost 1990; 63 (3) 482-487
93 Vulin AI, Stanley FM. Oxidative stress activates the plasminogen activator inhibitor type 1 (PAI-1) promoter through an AP-1 response element and cooperates with insulin for additive effects on PAI-1 transcription. J Biol Chem 2004; 279 (24) 25172-25178
94 Konkle BA, Schuster SJ, Kelly MD , et al. Plasminogen activator inhibitor-1 messenger RNA expression is induced in rat hepatocytes in vivo by dexamethasone. Blood 1992; 79 (10) 2636-2642
95 Yamamoto K, Shimokawa T, Yi H , et al. Aging and obesity augment the stress-induced expression of tissue factor gene in the mouse. Blood 2002; 100 (12) 4011-4018
96 Takeshita K, Yamamoto K, Ito M , et al. Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, “Klotho” mouse. Semin Thromb Hemost 2002; 28 (6) 545-554
97 Goldstein S, Moerman EJ, Fujii S, Sobel BE. Overexpression of plasminogen activator inhibitor type-1 in senescent fibroblasts from normal subjects and those with Werner syndrome. J Cell Physiol 1994; 161 (3) 571-579
98 Mu XC, Higgins PJ. Differential growth state-dependent regulation of plasminogen activator inhibitor type-1 expression in senescent IMR-90 human diploid fibroblasts. J Cell Physiol 1995; 165 (3) 647-657
99 Kunz C, Pebler S, Otte J, von der Ahe D. Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53. Nucleic Acids Res 1995; 23 (18) 3710-3717
100 Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol 2006; 8 (8) 877-884