Regulation of plasminogen activator inhibitor type 1 gene expression by inflammatory mediators and statins

Egbert K. O. Kruithof

doi:10.1160/TH08-04-0269

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(06): 969-975
DOI: 10.1160/TH08-04-0269

Theme Issue Article

Schattauer GmbH

Regulation of plasminogen activator inhibitor type 1 gene expression by inflammatory mediators and statins

Authors

Egbert K. O. Kruithof

¹Division of Angiology and Hemostasis, University Hospital, Geneva, Switzerland

Abstract

Summary

Elevated plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1), also named serpin E1, are encountered in patients with thrombophilia, atherosclerosis, septicemia and the metabolic syndrome and may be associated with an increased risk of complications. Expression of PAI-1 is increased by inflammatory stimuli and decreased by statins, drugs widely used in patients with cardiovascular disease. Increased expression of PAI-1 by inflammatory stimuli is mediated by a large variety of signal transduction pathways, which include the NF-κB and MAP kinase pathways. The downregulating effect of statins on PAI-1 expression is dependent on the inhibition of Rho family proteins and may involve an activation of PI-3 kinase/Akt signaling pathways. In this review we summarize the findings on the effect of inflammation and statins on PAI-1 expression.

Keywords

Plasminogen activator inhibitor type 1 - gene regulation - inflammation - statins

Full Text

References

References
1 Hoekstra T, Geleijnse JM, Schouten EG. et al. Plasminogen activator inhibitor-type 1: its plasma determinants and relation with cardiovascular risk. Thromb Haemost 2004; 91: 861-872.
2 Lijnen HR. Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost 2005; 03: 35-45.
3 Hermans PW, Hazelzet JA. Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. Clin Infect Dis 2005; 41 (Suppl. 07) S453-458.
4 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006; 26: 2200-2207.
5 Westrick RJ, Eitzman DT. Plasminogen activator inhibitor-1 in vascular thrombosis. Curr Drug Targets 2007; 08: 996-1002.
6 Vaughan DE, De Taeye BM, Eren M. PAI-1 antagonists: predictable indications and unconventional applications. Curr Drug Targets 2007; 08: 962-970.
7 Balsara RD, Xu Z, Ploplis VA. Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in mice. Curr Drug Targets 2007; 08: 982-995.
8 Danø K, Behrendt N, Høyer-Hansen G, Johnsen M, Lund LR, Ploug M, Rømer J. Plasminogen activation and cancer. Thromb Haemost 2005; 93: 676-681.
9 Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost 2005; 93: 631-640.
10 Pralong G, Calandra T, Glauser MP, Schellekens J, Verhoef J, Bachmann F, Kruithof EK. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-462.
11 Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27: 3-9.
12 van der Poll T, Levi M, Büller HR, van Deventer SJ, de Boer JP, Hack CE, ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991; 174: 729-732.
13 Kruithof EK, Mestries JC, Gascon MP, Ythier A. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation-effect of interleukin 6. Thromb Haemost 1997; 77: 905-910.
14 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.
15 Lupu F, Bergonzelli GE, Heim DA, Cousin E, Genton CY, Bachmann F, Kruithof EK. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13: 1090-1100.
16 Padró T, Quax PH, van den Hoogen CM, Roholl P, Verheijen JH, Emeis JJ. Tissue-type plasminogen activator and its inhibitor in rat aorta. Effect of endotoxin. Arterioscler Thromb 1994; 14: 1459-1465.
17 Rega G, Kaun C, Weiss TW. et al. Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue. Circulation 2005; 111: 1938-1945.
18 Schleef RR, Bevilacqua MP, Sawdey M. et al. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. J Biol Chem 1988; 263: 5797-5803.
19 Sawdey M, Podor TJ, Loskutoff DJ. Regulation of type 1 plasminogen activator inhibitor gene expression in cultured bovine aortic endothelial cells. Induction by transforming growth factor-beta, lipopolysaccharide, and tumor necrosis factor-alpha. J Biol Chem 1989; 264: 10396-10401.
20 van Hinsbergh VW, Kooistra T, van den Berg EA. et al. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 1988; 72: 1467-1473.
21 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-alpha and lipopolysaccharide. J Clin Invest 1996; 97: 37-46.
22 Lee E, Vaughan DE, Parikh SH. et al. Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells. Circ Res 1996; 78: 44-49.
23 Wiesbauer F, Kaun C, Zorn G, Maurer G, Huber K, Wojta J. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br J Pharmacol 2002; 135: 284-292.
24 Dong J, Fujii S, Imagawa S, Matsumoto S, Matsushita M, Todo S, Tsutsui H, Sobel BE. IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBPdelta. Am J Physiol Cell Physiol 2007; 292: C209-215.
25 Peiretti F, Fossat C, Anfosso F. et al. Increase in cytosolic calcium upregulates the synthesis of type 1 plasminogen activator inhibitor in the human histiocytic cell line U937. Blood 1996; 87: 162-163.
26 Schindler JF, Monahan JB, Smith WG. p38 pathway kinases as anti-inflammatory drug targets. J Dent Res 2007; 86: 800-811.
27 Liu SF, Malik AB. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 2006; 290: L622-L645.
28 Hamaguchi E, Takamura T, Shimizu A. et al. Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells. J Pharmacol Exp Ther 2003; 307: 987-994.
29 Hou B, Eren M, Painter CA. et al. Tumor necrosis factor alpha activates the human plasminogen activator inhibitor-1 gene through a distal nuclear factor kappaB site. J Biol Chem 2004; 279: 18127-18136.
30 Mukai Y, Wang CY, Rikitake Y. et al. Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells. Am J Physiol Heart Circ Physiol 2007; 292: H1937-942.
31 Pandey M, Loskutoff DJ, Samad F. Molecular mechanisms of tumor necrosis factor-alpha-mediated plasminogen activator inhibitor-1 expression in adipocytes. FASEB J 2005; 19: 1317-1319.
32 Kishida M, Urakaze M, Takata M. et al. PGE1 inhibits the expression of PAI-1 mRNA induced by TNFalpha in human mesangial cells. Exp Clin Endocrinol Diabetes 2005; 113: 365-371.
33 Hsieh YS, Yang SF, Lue KH, Chu SC, Li TJ, Lu KH. Upregulation of urokinase-type plasminogen activator and inhibitor and gelatinase expression via3 mitogenactivated protein kinases and PI3K pathways during the early development of osteoarthritis. J Rheumatol 2007; 34: 785-793.
34 Chen YQ, Su M, Walia RR. et al. Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. J Biol Chem 1998; 273: 8225-8231.
35 Fink T, Kazlauskas A, Poellinger L. et al. Identification ofa tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood 2002; 99: 2077-2083.
36 Eriksson P, Nilsson L, Karpe F. et al. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 1998; 18: 20-26.
37 Dennler S, Itoh S, Vivien D. et al. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998; 17: 3091-3100.
38 Chen YQ, Sloan-Lancaster J, Berg DT. et al. Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells. Thromb Haemost 2001; 86: 1563-1572.
39 Gruber F, Hufnagl P, Hofer-Warbinek R. et al. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor1 (PAI-1) promoter regulates TNF alpha -induced PAI-1 expression. Blood 2003; 101: 3042-3048.
40 Swiatkowska M, Pawlowska Z, Szemraj J. et al. Cerivastatin, a HMG-CoA reductase inhibitor, reduces plasminogen activator inhibitor-1 (PAI-1) expression in endothelial cells by down-regulation of cellular signaling and the inhibition of PAI-1 promoter activity. Jpn J Pharmacol 2002; 90: 337-344.
41 Dawson SJ, Wiman B, Hamsten A. et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-10745.
42 The LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349-1357.
43 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21: 1712-1719.
44 Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 2006; 16: 522-529.
45 Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE 2004; 250: RE13.
46 Wei J, Ma C, Wang X. Simvastatin inhibits tissue factor and plasminogen activator inhibitor-1 expression of glomerular mesangial cells in hypercholesterolemic rabbits. Biomed Res 2006; 27: 149-155.
47 Essig M, Nguyen G, Prié D. et al. 3-Hydroxy- 3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res 1998; 83: 683-690.
48 Lopez S, Peiretti F, Bonardo B. et al. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 2000; 152: 359-366.
49 Mussoni L, Banfi C, Sironi L. et al. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost 2000; 84: 59-64.
50 Kunieda Y, Nakagawa K, Nishimura H, Kato H, Ukimura N, Yano S, Kawano H, Kimura S, Nakagawa M, Tsuji H. HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells. Thromb Res 2003; 110: 227-234.
51 Markle RA, Han J, Summers BD. et al. Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells. J Cell Biochem 2003; 90: 23-32.
52 Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20: 556-562.
53 Demyanets S, Kaun C, Maurer G, Huber K, Wojta J. Statins modulate expression of components of the plasminogen activator/plasmin system in human cardiac myocytes in vitro. J Thromb Haemost 2006; 04: 476-479.
54 Haslinger B, Goedde MF, Toet KH. et al. Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney Int 2002; 62: 1611-1619.
55 Laumen H, Skurk T, Hauner H. The HMG-CoA reductase inhibitor rosuvastatin inhibits plasminogen activator inhibitor-1 expression and secretion in human adipocytes. Atherosclerosis 2008; 196: 565-573.
56 Li JQ, Zhao SP, Li QZ. et al. Atorvastatin reduces plasminogen activator inhibitor-1 expression in adipose tissue of atherosclerotic rabbits. Clin Chim Acta 2006; 370: 57-62.
57 Essig M, Vrtovsnik F, Nguyen G, Sraer JD, Friedlander G. Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins. J Am Soc Nephrol 1998; 09: 1377-1388.
58 Ishibashi T, Nagata K, Ohkawara H. et al. Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes. Biochim Biophys Acta 2002; 1590: 123-130.
59 Lopez S, Peiretti F, Bonardo B, Deprez-Beauclair P, Laouenan H, Juhan-Vague I, Nalbone G. Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages. J Cardiovasc Pharmacol 2001; 37: 762-768.
60 Asahi M, Huang Z, Thomas S. et al. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab 2005; 25: 722-729.
61 Dichtl W, Dulak J, Frick M. et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003; 23: 58-63.
62 Haslinger B, Kleemann R, Toet KH. et al. Simvastatin suppresses tissue factor expression and increases fibrinolytic activity in tumor necrosis factor-alpha-activated human peritoneal mesothelial cells. Kidney Int 2003; 63: 2065-2074.
63 Song CY, Kim BC, Lee HS. Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factorbeta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells. Transl Res 2008; 151: 27-35.
64 Loirand G, Guérin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006; 98: 322-334.
65 McKinsey TA, Kass DA. Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov 2007; 06: 617-635.
66 Hiroki J, Shimokawa H, Higashi M. et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004; 37: 537-546.
67 Takeda K, Ichiki T, Tokunou T. et al. Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. Arterioscler Thromb Vasc Biol 2001; 21: 868-873.
68 Rikitake Y, Liao JK. Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells. Circulation 2005; 111: 3261-3268.
69 Iwasaki H, Okamoto R, Kato S. et al. High glucose induces plasminogen activator inhibitor-1 expression through Rho/Rho-kinase-mediated NF-kappaB activation in bovine aortic endothelial cells. Atherosclerosis 2008; 196: 22-28.
70 Samarakoon R, Higgins SP, Higgins CE. et al. TGFbeta1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60(c-src)/EGFR (Y845) and Rho/ROCK signaling. J Mol Cell Cardiol 2008; 44: 527-538.
71 Rivera P, Ocaranza MP, Lavandero S. et al. Rho kinase activation and gene expression related to vascular remodeling in normotensive rats with high angiotensin I converting enzyme levels. Hypertension 2007; 50: 792-798.
72 Skaletz-Rorowski A, Lutchman M, Kureishi Y. et al. HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc Res 2003; 57: 253-264.
73 Whitley BR, Beaulieu LM, Carter JC. et al. Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells. Gynecol Oncol 2007; 104: 470-479.
74 Chatah NE, Abrams CS. G-protein-coupled receptor activation induces the membrane translocation and activation of phosphatidylinositol-4-phosphate 5-kinase I alpha by a Rac- and Rho-dependent pathway. J Biol Chem 2001; 276: 34059-34065.
75 Fukuyama R, Fujita T, Azuma Y. et al. Statins inhibit osteoblast migration by inhibiting Rac-Akt signaling. Biochem Biophys Res Commun 2004; 315: 636-642.
76 Welch HC, Coadwell WJ, Stephens LR. et al. Phosphoinositide 3-kinase-dependent activation of Rac. FEBS Lett 2003; 546: 93-97.