Plasminogen activator inhibitor-1: The double-edged sword in apoptosis

Summary

Plasminogen activator inhibitor type-1 (PAI-1) is a multi-functional protein. It is a fast-acting inhibitor of plasminogen activators; urokinase-plasminogen activator and tissue type plasminogen activator, and also plays an important role in regulating cell proliferation, adhesion, migration, and signal transduction pathways.These biological events are important processes during angiogenesis and restenosis. PAI-1 has been shown to regulate proliferation, migration, and apoptosis of vascular smooth muscle cells and endothelial cells.The ability of PAI-1 to regulate cellular proliferation and migration has been attributed to its ability to control plasmin production, modify signaling pathways, and its inherent multifactorial ability to bind to vitronectin and lipoprotein receptor-related protein.However,the mechanism by which PAI-1 regulates the apoptotic pathway is not well understood. Evidence from the literature suggests that PAI-1 or its deficiency alters key signalling pathways, such as the PI3-k/Akt and the Jak/STAT pathways, and is involved in maintaining endothelial cell integrity thereby regulating cell death. Other investigators have demonstrated that PAI-1 directly binds to caspases as a mechanism of PAI-1-mediated cellular apoptosis. Moreover, results from studies assessing the role of PAI-1 in apoptosis have suggested that PAI-1 can exert pathogenic or protective effects, which may be related to the disease model or type of injury employed.

Keywords

Apoptosis - fibrinolysis inhibitors - plasminogen activator inhibitors

• References

• 1 Blasi F. uPA, uPAR, PAI-1: Key intersection of proteolytic, adhesive and chemotactic highways?. Immunol Today 1997; 18: 415-417.
• 2 Foekens JA, Peters H, Look M. et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000; 60: 636-643.
• 3 Devy L, Blacher S, Grignet-Debrus C. et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16: 147-154.
• 4 Han DK, Haudenschild C, Hong M. et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol 1995; 147: 267-277.
• 5 Bauriedel G, Hutter R, Welsch U. et al. Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability. Cardiovasc Res 1999; 41: 480-488.
• 6 Bennett MR, Evan G, Schwartz S. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 1995; 95: 2266-2274.
• 7 Isner JM, Kearney M, Bortman S. et al. Apoptosis in human atherosclerosis and restenosis. Circulation 1995; 91: 2703-2711.
• 8 Kim HS, Huang K, Seo J. et al. Apoptosis and regulation of Bax and Bcl-X proteins during human neonatal vascular remodeling. Arterioscler Thromb Vasc Biol 2000; 20: 957-963.
• 9 Meilhac O, Ho-Tin-Noé B, Houard X. et al. Pericellular plasmin induces smooth muscle cell anoikis. FASEB J 2003; 17: 1301-1303.
• 10 Davis J, Wagner M, Zhang W. et al. Amyloid betaprotein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. J Biol Chem 2003; 278: 19054-19061.
• 11 Melchor JP, Pawlak R, Strickland S. The tissue plasminogen activator-plasminogen proteolytic cas-cade accelerates amyloid-β (Aβ) degradation and inhibits Aβ-induced neurodegeneration. J Neuroscience 2003; 03: 8867-8871.
• 12 Flavin MP, Zhao G, Ho LT. Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro. GLIA 2000; 29: 347-354.
• 13 Rabbani SA, Mazar A, Bernier S. et al. Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J Biol Chem 1992; 267: 14151-14156.
• 14 Degryse B, Orlando S, Resnati M. et al. Urokinase/ urokinase receptor and vitronectin/alpha(v)beta(3) integrin induce chemotaxis and cytoskeleton reorganization through different signalling pathways. Oncogene 2001; 20: 2032-2043.
• 15 Kirchheimer JC, Wojta J, Christ G. et al. Proliferation of a human epidermal tumor cell line stimulated by urokinase. FASEB J 1987; 01: 125-128.
• 16 Crowley CW, Cohen R, Lucas B. et al. Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci USA 1993; 90: 5021-5025.
• 17 Pulukuri SM, Gondi C, Lakka S. et al. RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival, and tumorigenicity in vivo. J Biol Chem 2005; 280: 36529-36540.
• 18 Subramanian R, Gondi CS, Lakka SS. et al. siRNAmediated simultaneous downregulation of uPA and its receptor inhibits angiogenesis and invasiveness triggering apoptosis in breast cancer cells. Int J Oncol 2006; 28: 831-839.
• 19 Alfano D, Iaccarino I, Stoppelli M. Urokinase signalling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 2006; 281: 17758-17767.
• 20 Mitchell JW, Baik N, Castellino FJ. et al. Plasminogen inhibits TNFalpha-induced apoptosis in monocytes. Blood 2006; 107: 4383-4390.
• 21 Stephens RW, Nielsen H, Christensen I. et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 1999; 91: 869-874.
• 22 Sier CF, Stephens R, Bizik J. et al. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res 1998; 58: 1843-1849.
• 23 Pappot H, Høyer-Hansen G, Rønne E. et al. Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients. Eur J Cancer 1997; 33: 867-872.
• 24 Grøndahl-Hansen J, Peters H, van Putten W. et al. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res 1995; 01: 1079-1087.
• 25 Holst-Hansen C, Johannessen B, Høyer-Hansen G. et al. Urokinase-type plasminogen activation in three human breast cancer cell lines correlates with their in vitro invasiveness. Clin Exp Metastasis 1996; 14: 297-307.
• 26 Grøndahl-Hansen J, Christensen I, Briand P. et al. Plasminogen activator inhibitor type 1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients. Clin Cancer Res 1997; 03: 233-239.
• 27 Jänicke F, Schmitt M, Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type 1 inhibitor in breast cancer. Semin Thromb Hemost 1991; 17: 303-312.
• 28 Borgfeldt C, Hansson S, Gustavsson B. et al. Dedifferentiation of serous ovarian cancer from cystic to solid tumors is associated with increased expression of mRNA for urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1). Int J Cancer 2001; 92: 497-502.
• 29 Liu G, Shuman M, Cohen R. Co-expression of urokinase, urokinase receptor and PAI- 1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer 1995; 60: 501-506.
• 30 Juhan-Vague I, Roul C, Alessi MC. et al. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients--relationship with plasma insulin. Thromb Haemost 1989; 61: 370-373.
• 31 Bajou K, Noël A, Gerard RD. et al. Absence of host plasminogen activator inhibitor-1 prevents cancer invasion and vascularization. Nat Med 1998; 04: 923-928.
• 32 Gutierrez LS, Schulman A, Brito-Robinson T. et al. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 2000; 60: 5839-5847.
• 33 Devy L, Blacher S, Grignet-Debrus C. et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16: 147-154.
• 34 Rømer MU, Kirkebjerg Due A, Knud Larsen J. et al. Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis. Thromb Haemost 2005; 94: 859-866.
• 35 Lambert V, Munaut C, Noël A. et al. Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J 2001; 15: 1021-1027.
• 36 Soff GA, Sanderowitz J, Gately S. et al. Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest 1995; 96: 2593-2500.
• 37 Stefansson S, Petitclerc E, Wong MK. et al. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 2001; 276: 8135-8141.
• 38 Swiercz R, Keck RW, Skrzypczak-Jankun E. et al. Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostate cancer xenografts in SCID mice. Oncol Rep 2001; 08: 463-470.
• 39 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: 232-237.
• 40 Lambert V, Munaut C, Carmeliet P. et al. Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials. Invest Ophthalmol Vis Sci 2003; 44: 2791-2797.
• 41 Deng G, Curriden S, Wang S. et al. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release?. J Cell Biol 1996; 134: 1563-1571.
• 42 Waltz DA, Natkin L, Fujita R. et al. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest 1997; 100: 58-67.
• 43 Foekens JA, Schmitt M, van Putten W. et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 1994; 12: 1648-1658.
• 44 Kuhn W, Pache L, Schmalfeldt B. et al. Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. Gynecol Oncol 1994; 55: 401-409.
• 45 Pedersen H, Grøndahl-Hansen J, Francis D. et al. Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res 1994; 54: 120-123.
• 46 Sier CF, Vloedgraven H, Ganesh S. et al. Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis. Gastroenterology 1994; 107: 1449-1456.
• 47 Hofmann R, Lehmer A, Buresch M. et al. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer 1996; 78: 487-492.
• 48 Sugiura Y, Ma L, Sun B. et al. The plasminogenplasminogen activator (PA) system in neuroblastoma: role of PA inhibitor-1 in metastasis. Cancer Res 1999; 59: 1327-1336.
• 49 Bashar H, Urano T, Fukuta K. et al. Plasminogen activators and plasminogen activator inhibitor1 in urinary tract cancer. Urol Int 1994; 52: 4-8.
• 50 Casslén B, Bossmar T, Lecander I. et al. Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer. Eur J Cancer 1994; 30A: 1302-1309.
• 51 Cajot JF, Bamat J, Bergonzelli G. et al. Plasminogen-activator inhibitor type 1 is a potent natural inhibitor of extracellular matrix degradation by fibrosarcoma and colon carcinoma cells. Proc Natl Acad Sci USA 1990; 87: 6939-6943.
• 52 Alizadeh H, Ma D, Berman M. et al. Tissue-type plasminogen activator-induced invasion and metastasis of murine melanomas. Curr Eye Res 1995; 14: 449-458.
• 53 Bajou K, Maillard C, Jost M. et al. Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene 2004; 23: 6986-6990.
• 54 Kwaan HC, Wang J, Svoboda K. et al. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 2000; 82: 1702-1708.
• 55 Lademann U, Rømer MU, Jensen PB. et al. Malignant transformation of wild-type but not plasminogen activator inhibitor-1 gene-deficient fibroblasts decreases cellular sensitivity to chemotherapy-mediated apoptosis. Eur J Cancer 2005; 41: 1095-1100.
• 56 Suwa D, Konno H, Tanaka T. et al. Intraperitoneal infusion of recombinant plasminogen activator inhibitor type 2 induced apoptosis in implanted human colon cancer and inhibited its growth and liver metastasis. Anticancer Res 2008; 28: 693-698.
• 57 Li Y, Rizvi S, Ranson M. et al. 213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model. Br J Cancer 2002; 86: 1197-1203.
• 58 Chen SC, Henry D, Reczek P. et al. Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther 2008; 07: 1227-1236.
• 59 Stefansson S, Su E, Ishigami S. et al. The contributions of integrin affinity and integrin-cytoskeletal engagement in endothelial and smooth muscle cell adhesion to vitronectin. J Biol Chem 2007; 282: 15679-15689.
• 60 Isogai C, Laug W, Shimada H. et al. Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res 2001; 61: 5587-5594.
• 61 Al-Fakhri N, Chavakis T, Schmidt-Wöll T. et al. Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. Biol Chem 2003; 384: 423-435.
• 62 Ploplis VA, Balsara R, Sandoval-Cooper M. et al. Enhanced in vitro proliferation of aortic endothelial cells from plasminogen activator inhibitor-1-deficient mice. J Biol Chem 2004; 279: 6143-6151.
• 63 Balsara RD, Castellino F, Ploplis V. A novel function of plasminogen activator inhibitor-1 in modulation of the AKT pathway in wild-type and plasminogen activator inhibitor-1-deficient endothelial cells. J Biol Chem 2006; 281: 22527-22536.
• 64 Hanke H, Strohschneider T, Oberhoff M. et al. Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty. Circ Res 1990; 67: 651-659.
• 65 O’Brien ER, Alpers C, Stewart D. et al. Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy. Circ Res 1993; 73: 223-231.
• 66 Malik N, Francis S, Holt C. et al. Apoptosis and cell proliferation after porcine coronary angioplasty. Circulation 1998; 98: 1657-1665.
• 67 Nordt TK, Sawa H, Fujii S. et al. 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: 1535-1543.
• 68 Sobel BE, Woodcock-Mitchell J, Schneider D. et al. 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: 2213-2221.
• 69 Pandolfi A, Cetrullo D, Polishuck R. et al. Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thromb Vasc Biol 2001; 21: 1378-1382.
• 70 Chen Y, Kelm R, Budd R. et al. Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem 2004; 92: 178-188.
• 71 Komiyama T, Ray CA, Pickup DJ. et al. Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition. J Biol Chem 1994; 269: 19331-19337.
• 72 Annand RR, Dahlen JR, Sprecher CA. et al. Caspase-1 (interleukin-1beta-converting enzyme) is inhibited by the human serpin analogue proteinase inhibitor 9. Biochem J 1999; 342: 655-665.
• 73 Ray CA, Black RA, Kronheim SR. et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 1992; 69: 597-604.
• 74 Chen Y, Budd R, Kelm R. et al. Augmentation of proliferation of vascular smooth muscle cells by plasminogen activator inhibitor type 1. Arterioscler Thromb Vasc Biol 2006; 26: 1777-1783.
• 75 Rossignol P, Angles-Cano E, Lijnen H. Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis. Thromb Haemost 2006; 96: 665-670.
• 76 Rossignol P, Luttun A, Martin-Ventura L. et al. Plasminogen activation: a mediator of vascular smooth muscle cell apoptosis in atherosclerotic plaques. J Thromb Haemost 2006; 04: 664-670.
• 77 Tomasek JJ, Gabbiani G, Hinz B. et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 03: 349-363.
• 78 Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995; 146: 56-66.
• 79 Horowitz JC, Rogers D, Simon R. et al. Plasminogen Activation–Induced Pericellular Fibronectin Proteolysis Promotes Fibroblast Apoptosis. Am J Respir Cell Mol Biol 2008; 38: 78-87.
• 80 Ploplis VA, Castellino F. Attenuation of neointima formation following arterial injury in PAI-1 deficient mice. Ann NY Acad Sci 2001; 936: 466-468.
• 81 Peng L, Bhatia N, Parker A. et al. Endogenous vitronectin and plasminogen activator inhibitor-1 promote neointima formation in murine carotid arteries. Arterioscler Thromb Vasc Biol 2002; 22: 934-939.
• 82 Baranes D, Lederfein Y, Huang M. et al Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 1998; 21: 813-825.
• 83 Fiumelli H, Jabaudon D, Magistretti P. et al. BDNF stimulates expression, activity and release of tissuetype plasminogen activator in mouse cortical neurons. Eur J Neurosc 1999; 11: 1639-1646.
• 84 Tsirka SE, Gualandris A, Amaral D. et al. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377: 340-344.
• 85 Tsirka SE, Rogove A, Strickland S. Neuronal cell death and tPA. Nature 1996; 384: 123-124.
• 86 Rao JS, Chen M, Festoff B. Plasminogen activator inhibitor 1, the primary regulator of fibrinolysis, in normal human cerebrospinal fluid. J Neurosci Res 1993; 34: 340-345.
• 87 Rao JS, Rayford A, Morantz R. et al. Increased levels of plasminogen activator inhibitor-1 (PAI-1) in human brain tumors. J Neurooncol 1993; 17: 215-221.
• 88 Sutton R, Keohane M, VanderBerg S. et al. Plasminogen activator inhibitor-1 in the cerebrospinal fluid as an index of neurological disease. Blood Coagul Fibrinolysis 1994; 05: 167-171.
• 89 Akenami FO, Koskiniemi M, Färkkilä M. et al. Cerebrospinal fluid plasminogen activator inhibitor-1 in patients with neurological disease. J Clin Pathol 1997; 50: 157-160.
• 90 Arai Y, Kubota T, Nakagawa T. et al. Production of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in human brain tumours. Acta Neurochir (Wien) 1998; 140: 377-385.
• 91 Landau BJ, Kwaan H, Verrusio E. et al. Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant human brain tumors. Cancer Res 1994; 54: 1105-1108.
• 92 Iwadate Y, Hayama M, Adachi A. et al. High serum level of plasminogen activator inhibitor-1 predicts histological grade of intracerebral gliomas. Anticancer Res 2008; 28: 415-418.
• 93 Soeda S, Oda M, Ochiai T. et al. Deficient release of plasminogen activator inhibitor-1 from astrocytes triggers apoptosis in neuronal cells. Brain Res Mol Brain Res 2001; 91: 96-103.
• 94 Soeda S, Shinomiya K, Ochiai T. et al. Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun pathways. Neuroscience 2006; 141: 101-108.
• 95 Docagne F, Nicole O, Gabriel C. et al. Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis. Mol Cell Neurosci 2002; 21: 634-644.
• 96 Gabriel C, Ali C, Lesné S. et al. Transforming growth factor alpha-induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity. FASEB J 2003; 17: 277-279.
• 97 Nagai N, De Mol M, Lijnen H. et al. Role of plasminogen system components in focal cerebral ischemic infarction: a gene targeting and gene transfer study in mice. Circulation 1999; 99: 2440-2444.
• 98 Launay S, Maubert E, Lebeurrier N. et al. HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival. Cell Death Differ. 2008 prepub online.
• 99 Degryse B, Neels JG, Czekay RP. et al. The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 2004; 279: 22595-22604.
• 100 Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99: 995-1000.
• 101 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: 777-784.
• 102 Beaulieu LM, Whitley BR, Wiesner TF. et al. Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor-1 cycle. Bioessays 2007; 29: 1029-1038.