Thrombin and protease-activated receptors (PARs) in atherothrombosis

Lluis Martorell; José Martínez-González; Cristina Rodríguez; Maurizio Gentile; Olivier Calvayrac; Lina Badimon

doi:10.1160/TH07-08-0481

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 99(02): 305-315
DOI: 10.1160/TH07-08-0481

Review Article

Schattauer GmbH

Thrombin and protease-activated receptors (PARs) in atherothrombosis

Lluis Martorell

¹Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

,

José Martínez-González

¹Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

,

Cristina Rodríguez

¹Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

,

Maurizio Gentile

¹Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

,

Olivier Calvayrac

¹Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

,

Lina Badimon

¹Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

› Institutsangaben

Abstract

Summary

Thrombin is a multifunctional serine protease generated at the site of vascular injury that transforms fibrinogen into fibrin, activates blood platelets and elicits multiple effects on a variety of cell types including endothelial cells, vascular smooth muscle cells (VSMC), monocytes,T lymphocytes and fibroblasts. Cellular effects of thrombin are mediated by protease-activated receptors (PARs), members of the G protein-coupled receptors that carry their own ligand which remains cryptic until unmasked by proteolytic cleavage. Thrombin signalling in platelets contributes to haemostasis and thrombosis. In normal arteries PARs are mainly expressed in endothelial cells, while their expression in VSMC is limited. Endothelial PARs participate in the regulation of vascular tone, vascular permeability and endothelial secretory activity while in VSMC they mediate contraction, migration, proliferation, hypertrophy and production of extra-cellular matrix. PARs contribute to the pro-inflammatory phenotype observed in endothelial dysfunction and their up-regulation inVSMC seems to be a key element in the pathogenesis of atherosclerosis and restenosis. In the last years a myriad of studies have emphasized the critical role of PAR signalling in thrombin mediated effects in haemostasis, inflammation, cancer and embryonic development. Lately, PARs have become a therapeutic target to inhibit platelet aggregation and thrombosis. Early data from a clinical trial (TRA-PCI) to evaluate safety and efficacy of a potent new oral thrombin receptor antagonist (TRA) have promisingly indicated that overallTRA treatment reduces adverse event rates without an increase in bleeding risk. In this paper we review cellular responses triggered by thrombin and their implication in vascular pathophysiology.

Keywords

Atherothombosis - thrombin - protease-activated receptors - gene expression

Volltext

Referenzen

References
1 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (Part I). New Engl J Med 1992; 326: 242-250.
2 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and acute coronary syndromes (Part II). New Engl J Med 1992; 326: 310-318.
3 Badimon L, Meyer BJ, Badimon JJ. Thrombin in arterial thrombosis. Haemostasis 1994; 24: 69-80.
4 Wouwer MV, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system. Integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24: 1374-1384.
5 Bock SC. Antithrombin III and heparin cofactor II. Haemostasis and Thrombosis: Basic principles and clinical practice. 2001: 321-333.
6 Vu T-KH, Hung DT, Wheaton VI. et al. Molecular of functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-1068.
7 Hirano K. The roles of protease-activated receptors in the vascular physiology and pathophysiology. Arteriscler Thromb Vasc Biol 2007; 27: 27-36.
8 Majumdar M, Tarui T, Shi B. et al. Plasmin-induced migration requires signalling through protease-activated receptor1 and integrin alpha(9)beta(1). J Biol Chem 2004; 279: 37528-37534.
9 Ishihara H, Connolly AJ, Zeng D. et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997; 386: 502-506.
10 Nakanishi-Matsui M, Zheng YW, Sulciner DJ. et al. PAR3 is a coactivator for PAR4 activation by thrombin. Nature 2000; 404: 609-613.
11 O'Brien PJ, Prevost N, Molino M. et al. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem 2000; 275: 13502-13509.
12 Riewald M, Petrovan RJ, Donner A. et al. Activation of endothelial cell protease activated receptor 1 by protein C pathway. Science 2002; 296: 1880-1882.
13 Coughlin SR. Thrombin signalling and proteaseactivated receptors. Nature 2000; 407: 258-264.
14 Coughlin SR. Protease-activated receptors in haemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3: 1800-1814.
15 Seiler SM, Bernatowicz MS. Peptide-derived protease-activated receptor-1 (PAR-1) antagonists. Curr Med Chem Cardiovasc Hematol Agents 2003; 1: 1-11.
16 Trejo J, Altschuler Y, Fu HW. et al. Protease-activated receptor-1 down regulation: a mutant HeLa cell line suggests novel requirements for PAR1 phosphorylation and recruitment to clathrin-coated pits. J Biol Chem 2000; 275: 31255-31265.
17 Hein L, Ishii K, Coughlin SR. et al. Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for re-sensitization of a G protein-coupled receptor. J Biol Chem 1994; 269: 27719-27726.
18 Yufu T, Hirano K, Bi D. et al. Rac1 regulation of surface expression of protease-activated receptor-1 and responsiveness to thrombin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2005; 25: 1506-1511.
19 Badimon JJ, Weng D, Chesebro JH. et al. Platelet deposition induced by severely damaged vessel wall is inhibited by a boroarginine synthetic peptide with antithrombin activity. Thromb Haemost 1994; 71: 511-516.
20 Steinberg SF. The cardiovascular actions of protease-activated receptors. Mol Pharmacol 2005; 67: 2-11.
21 Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114: 1070-1077.
22 Kahn ML, Zheng YW, Huang W. et al. A dual thrombin receptor system for platelet activation. Nature 1998; 394: 690-694.
23 Shapiro MJ, Weiss EJ, Faruqi TR. et al. Protease-activated receptors 1 and 4 are shut off with distinct kinetics after activation by thrombin. J Biol Chem 2000; 275: 25216-25221.
24 Andrews RK, Shen Y, Gardiner EE. et al. The glycoprotein Ib-IX-V complex in platelet adhesion and signalling. Thromb Haemost 1999; 82: 357-364.
25 Brass LF. Thrombin and platelet activation. Chest 2003; 124: 18S-25S.
26 Wu CC, Hwang TL, Liao CH. et al. The role of PAR4 in thrombin-induced thromboxane production in human platelets. Thromb Haemost 2003; 90: 299-308.
27 Weiss EJ, Hamilton JR, Lease KE. et al. Protection against thrombosis in mice lacking PAR3. Blood 2002; 100: 3240-3244.
28 Sambrano GR, Weiss EJ, Zheng YW. et al. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413: 74-78.
29 Covic L, Singh C, Smith H. et al. Role of the PAR4 thrombin receptor in stabilizing platelet-platelet aggregates as revealed by a patient with Hermansky-Pudlak syndrome. Thromb Haemost 2002; 87: 722-777.
30 Vretenbrant K, Ramström S, Bjerke M. et al. Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development. Thromb Haemost 2007; 97: 417-424.
31 Vanschoonbeek K, Feijge MA, Keuren JF. et al. Thrombin-induced hyperactivity of platelets of young stroke patients: involvement of thrombin receptors in the subject-dependent variability in Ca2+ signal generation. Thromb Haemost 2002; 88: 931-937.
32 Lin Z, Hamik A, Jain R. et al. Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation. Arterioscler Thromb Vasc Biol 2006; 26: 1185-1189.
33 Cottrell GS, Amadesi S, Schmidlin F, Bunnett N. Protease-activated receptor 2: activation, signalling and function. Biochem Soc Trans 2003; 31: 1191-1197.
34 Kataoka H, Hamilton JR, McKemy DD. et al. Protease-activated receptors 1 and 4 mediate thrombin signalling in endothelial cells. Blood 2003; 102: 3224-3231.
35 Tesfamariam B. Thrombin receptor-mediated vascular relaxation differentiated by a receptor antagonist and desensitization. Am J Physiol 1994; 267: H1962-H1967.
36 Mizuno O, Hirano K, Nishimura J. et al. Mechanism of endothelium-dependent relaxation induced by thrombin in the pig coronary artery. Eur J Pharmacol 1998; 351: 67-77.
37 Derkach DN, Ihara E, Hirano K. et al. Thrombin causes endothelium-dependent biphasic regulation of vascular tone in porcine renal interlobar artery. Br J Pharmacol 2000; 131: 1635-1642.
38 Ku DD, Zaleski JK. Receptor mechanism of thrombin-induced endothelium-dependent and endothelium independent coronary vascular effects in dogs. J Cardiovasc Pharmacol 1993; 22: 609-616.
39 Mizuno O, Kobayashi S, Hirano K. et al. Stimulusspecific alteration of the relationship between cytosolic Ca(2+)transients and nitric oxide production in endothelial cells ex vivo. Br J Pharmacol 2000; 130: 1140-1146.
40 Hamilton JR, Nguyen PB, Cocks TM. Atypical protease-activated receptor mediates endothelium-dependent relaxation of human coronary arteries. Circ Res 1998; 82: 1306-1311.
41 Momota F, Hirano K, Hirano M. et al. Involvement of Gi/o in the PAR-4-induced NO production in endothelial cells. Biochem Biophys Res Commun 2006; 342: 365-371.
42 De Garavilla L, Vergnolle N, Young SH. et al. Agonists of protease-activated receptor 1 induce plasma extravasation by a neurogenic mechanism. Br J Pharmacol 2001; 133: 975-987.
43 Nobe K, Sone T, Paul RJ. et al. Thrombin-induced force development in vascular endothelial cells: Contribution to alteration of permeability mediated by calcium-dependent and independent pathways. J Pharmacol Sci 2005; 99: 252-263.
44 Royo T, Martínez-González J, Vilahur G. et al. Differential intracellular trafficking of von Willebrand factor (vWF) and vWF propeptide in porcine endothelial cells lacking Weibel-Palade bodies and in human endothelial cells. Atherosclerosis 2003; 167: 55-63.
45 Görlach A, BelAiba RS, Hess J. et al. Thrombin activates the p21-activated kinase in pulmonary artery smooth muscle cells. Role in tissue factor expression. Thromb Haemost 2005; 93: 1168-1175.
46 Zhang JJ, Kelm RJ, Biswas P. et al. PECAM-1 modulates thrombin-induced tissue factor expression on endothelial cells. J Cell Physiol 2007; 210: 527-537.
47 Liu Y, Pelekanakis K, Woolkalis MJ. Thrombin and tumor necrosis factor alpha synergistically stimulate tissue factor expression in human endothelial cells: regulation through c-Fos and c-Jun. J Biol Chem 2004; 279: 36142-36147.
48 Minami T, Abid MR, Zhang J. et al. Thrombin stimulation of vascular adhesion molecule-1 in endothelial cells is mediated by protein kinase C (PKC)- delta-NF-kappa B and PKC-zeta-GATA signalling pathways. J Biol Chem 2003; 278: 6976-6984.
49 Minami T, Miura M, Aird W. et al. Thrombin-induced autoinhibitory factor, down syndrome critical region-1, attenuates NFAT-dependent vascular cell adhesion molecule-1 expression and inflammation in the endothelium. J Biol Chem 2006; 281: 20503-20520.
50 Martorell Ll, Martínez-González J, Crespo J. et al. Neuron-derived orphan receptor-1 (NOR-1) is induced by thrombin and mediates endotelial cell growth. J Thromb Haemost 2007; 5: 1766-1773.
51 Wilcox JN, Rodriguez J, Subramanian R. et al. Characterization of thrombin receptor expression during vascular lesion formation. Circ Res 1994; 75: 1029-1038.
52 Damiano BP, D'Andrea MR, de Garavilla L. et al. Increased expression of protease activated receptor-2 (PAR-2) in balloon-injured rat carotid artery. Thromb Haemost 1999; 81: 808-814.
53 Nelken NA, Soifer SJ, O'Keefe J. et al. Thrombin receptor expression in normal and atherosclerotic human arteries. J Clin Invest 1992; 90: 1614-1621.
54 Napoli C, de Nigris F, Wallace JL. et al. Evidence that protease activated receptor 2 expression is enhanced in human coronary atherosclerotic lesions. J Clin Pathol 2004; 57: 513-516.
55 Ku DD, Dai J. Expression of thrombin receptors in human atherosclerotic coronary arteries leads to an exaggerated vasoconstrictory response in vivo. J Cardiovasc Pharmacol 1997; 30: 649-657.
56 Chen LB, Buchanan JM. Mitogenic activity of blood components. Thrombin and prothrombin. Proc Natl Acad Sci USA 1975; 72: 131-135.
57 McNamara CA, Sarembock IJ, Gimple LW. et al. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by proteolytically activated receptor. J Clin Invest 1993; 91: 94-98.
58 Kanthou C, Kanse SM, Newman P. et al. Variability in the proliferative responsiveness of cultured human vascular smooth muscle cells to alpha-thrombin. Blood Coagul Fibrinolysis 1995; 6: 753-760.
59 Varela O, Martínez-González J, Badimon L. The response of smooth muscle cells to alpha-thrombin depends on its arterial origin: comparison among different species. Eur J Clin Invest 1998; 28: 313-323.
60 Ip JH, Fuster V, Badimon L. et al. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol 1990; 15: 1667-1687.
61 Fuster V, Falk E, Fallon JT. et al. The three processes leading to post PTCA restenosis: dependence on the lesion substrate. Thromb Haemost 1995; 74: 552-559.
62 Bretschneider E, Kaufmann R, Braun M. et al. Evidence for proteinase-activated receptor-4 (PAR-4) in human vascular smooth muscle cells. Br J Pharmacol 2001; 132: 1441-1446.
63 Rothman A, Wolner B, Button D. et al. Immediateearly gene expression in response to hypertrophic and proliferative stimuli in pulmonary arterial smooth muscle cells. J Biol Chem 1994; 269: 6399-6404.
64 Martínez-González J, Vinals M, Vidal F. et al. Mevalonate deprivation impairs IGF-I/insulin signalling in human vascular smooth muscle cells. Atherosclerosis 1997; 135: 213-223.
65 Lu C, Giordano FJ, Bao X. et al. Antisense fosB RNA inhibits thrombin-induced hypertrophy in cultured pulmonary arterial smooth muscle cells. Circulation 1998; 98: 596-603.
66 Madamanchi NR, Li S, Patterson C. et al. Thrombin regulates vascular smooth muscle cell growth and heat shock proteins via the JAK-STAT pathway. J Biol Chem 2001; 276: 18915-18924.
67 Pelletier S, Duhamel F, Coulombe P. et al. Rho family GTPases are required for activation of Jak/STAT signalling by G protein-coupled receptors. Mol Cell Biol 2003; 23: 1316-1333.
68 Liu Z, Dronadula N, Rao GN. A novel role for nuclear factor of activated T cells in receptor tyrosine kinase and G protein-coupled receptor agonist-induced vascular smooth muscle cell motility. J Biol Chem 2004; 279: 41218-41226.
69 Liu Z, Zhang C, Dronadula N. et al. Blockade of nuclear factor of activated T cells activation signalling suppresses balloon injury-induced neointima formation in a rat carotid artery model. J Biol Chem 2005; 280: 14700-14708.
70 Tokunou T, Ichiki T, Takeda K. et al. cAMP response element-binding protein mediates thrombin-induced proliferation of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2001; 21: 1764-1769.
71 Martínez-González J, Rius J, Castelló A. et al. Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation. Circ Res 2003; 92: 96-103.
72 Martínez-González J, Badimon L. The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells. Cardiovasc Res 2005; 65: 609-618.
73 Ossovskaya VS, Bunnet NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev 2004; 84: 579-621.
74 Barnes JA, Singh S, Gomes AV. Protease activated receptors in cardiovascular function and disease. Mol Cell Biochem 2004; 263: 227-239.
75 Chesebro JH, Zoldhelyi P, Badimon L. et al. Role of thrombin in arterial thrombosis: implications for therapy. Thromb Haemost 1991; 66: 1-5.
76 Badimon L, Chesebro JH, Badimon JJ. Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi. Circulation 1992; 86: III74-III85.
77 Fernández-Ortiz A, Badimon JJ, Falk E. et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 1994; 23: 1562-1569.
78 Toschi V, Gallo R, Lettino M. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-599.
79 Badimon L, Badimon JJ, Lassila R. et al. Thrombin regulation of platelet interaction with damaged vessel wall and isolated collagen type I at arterial flow conditions in a porcine model: effects of hirudins, heparin, and calcium chelation. Blood 1991; 78: 423-434.
80 Badimon JJ, Lettino M, Toschi V. et al. inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 9: 1780-1787.
81 Meyer BJ, Fernández-Ortiz A, Mailhac A. et al. Local delivery of r-hirudin by a double-balloon perfusion catheter prevents mural thrombosis and minimizes platelet deposition after angioplasty. Circulation 1994; 90: 2474-2480.
82 Meyer BJ, Badimon JJ, Chesebro JH. et al. Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin. Circulation 1998; 97: 681-685.
83 Derian CK, Damiano BP, Addo MF. et al. Blockage of the thrombin receptor protease-activated receptor-1 with small-molecule antagonist prevents thrombus formation and vascular occlusion in non human primates. J Pharmacol Exp Ther 2003; 304: 855-861.
84 Griffin CT, Srinivasan Y, Zheng YW. et al. A role for thrombin receptor signalling in endothelial cells during embryonic development. Science 2001; 293: 1666-1670.
85 Kempton CL, Harvey 3rd RD, Roberts HR. Novel therapeutic agents in the management of haemorrhage and thrombosis. Cardiovasc Hematol Agents Med Chem 2006; 4: 319-334.
86 Badimon L, Martínez-González J. Endotelial dysfunction. Rev Esp Cardiol 2006; 5: 21E-30E.
87 Hamilton JR, Frauman AG, Cocks TM. Increased expression of protease-activated receptor-2 (PAR2) and PAR4 in human coronary artery by inflammatory stimuli unveils endothelium-dependent relaxations to PAR2 and PAR4 agonists. Circ Res 2001; 89: 92-98.
88 Rosenberg JB, Foster PA, Kaufman RJ. et al. Intracellular trafficking of factor VIII to von Willebrand factor storage granules. J Clin Invest 1998; 101: 613-624.
89 Rosnoblet C, Vischer UM, Gerard RD. et al. Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human endothelial cells. Arterioscler Thromb Vasc Biol 1999; 19: 1796-1803.
90 Klarenbach SW, Chipiuk A, Nelson RC. et al. Differential actions of PAR-2 and PAR-1 in stimulating human endothelial cell exocytosis and permeability: The role of Rho-GTPases. Circ Res 2003; 92: 272-278.
91 Sugama Y, Malik AB. Thrombin receptor 14-amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P-selectin-dependent mechanism. Circ Res 1992; 71: 1015-1019
92 Kaplanski G, Marin V, Fabrigoule M. et al. Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intermolecular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106). Blood 1998; 92: 1259-1267.
93 Sapet C, Simoncini S, Loriod B. et al. Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspace-2. Blood 2006; 108: 1868-1876.
94 Piccin A, Murphy WG, Smith OP. Circulating microparticles: pathophysiology and clinical implications. Blood Rev 2007; 21: 157-171.
95 Bar-Shavit R, Benezra M, Eldor A. et al. Thrombin immobilized to extracellular matrix is a potent mitogen for vascular smooth muscle cells: nonenzymatic mode of action. Cell Reg 1990; 1: 453-463.
96 Meyer BJ, Badimon JJ, Mailhac A. et al. Inhibition of growth of thrombus on fresh mural thrombus. Targeting optimal therapy. Circulation 1994; 90: 2432-2438.
97 Martínez-González J, Berrozpe M, Varela O. et al. Heterogeneity of smooth muscle cells in advanced human atherosclerotic plaques: intimal smooth muscle cells expressing a fibroblast surface protein are highly activated by platelet-released products. Eur J Clin Invest 2001; 31: 939-949.
98 Dabbagh K, Laurent GJ, McAnulty RJ. et al. Thrombin stimulates smooth muscle cell pro-collagen synthesis and mRNA levels via PAR-1 mediated mechanism. Thromb Haemost 1998; 79: 405-407.
99 Cheung WM, D'Andrea MR, Andrade-Gordon P. et al. Altered vascular injury responses in mice deficient in protease-activated receptor-1. Arterioscler Thromb Vasc Biol 1999; 19: 3014-3024.
100 Shimizu T, Nishihira J, Watanabe H. et al. Macrophage migration inhibitory factor is induced by thrombin and factor Xa in endothelial cells. J Biol Chem 2004; 279: 13729-13737.
101 Tsopanoglou NE, Maragoudakis ME. On the mechanism of thrombin-induced angiogenesis: inhibition of attachment of endothelial cells on basement membrane components. Angiogenesis 1998; 1: 192-200.
102 Fernandez-Patron C, Zhang Y, Radomski MW. et al. Rapid release of matrix metalloproteinase (MMP)-2 by thrombin in the rat aorta: modulation by protein tyrosine kinase/phosphatase. Thromb Haemost 1999; 82: 1353-1357.
103 Maragoudakis ME, Kraniti N, Giannopoulou E. et al. Modulation of angiogenesis and progelatinase a by thrombin receptor mimetics and antagonists. Endothelium 2001; 8: 195-205.
104 Mirza H, Yatsula V, Bahou WF. The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells. J Clin Invest 1996; 97: 1705-1714.
105 Caunt M, Huang YQ, Brooks PC. et al. Thrombin induces neoangiogenesis in the chick chorioallantonic membrane. J Thromb Haemost 2003; 1: 2097-2102.
106 Tsopanoglou NE, Maragoudakis ME. On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptor. J Biol Chem 1999; 274: 23969-23976.
107 Huang YQ, Li JJ, Hu L. et al. Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes. Thromb Haemost 2001; 86: 1094-1098.
108 Mechtcheriakova D, Wlachos A, Holzmüller H, Binder BR, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1. Blood 1999; 93: 3811-3823.
109 Abe K, Shoji M, Chen J. et al. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999; 96: 8663-8668.
110 Uusitalo-Jarvinen H, Kurokawa T, Mueller BM, Andrade-Gordon P, Friedlander M, Ruf W. Role of protease activated receptor 1 and 2 signalling in hypoxiainduced angiogenesis. Arterioscler Thromb Vasc Biol 2007; 27: 1456-1462.
111 Dupuy E, Habib A, Lebret M. et al. Thrombin induces angiogenesis and vascular endothelial growth factor expression in human endothelial cells: possible relevance to HIF-1 alpha. J Thromb Haemost 2003; 1: 1096-1102.
112 Görlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R. Thrombin activates the hypoxia-inducible factor-1 signalling pathway in vascular smooth muscle cells: Role of p22phox-containing NAPDH oxidase. Circ Res 2001; 89: 47-54.
113 Bel Aiba RS, Djordjevic T, Bonello S. et al. Redox-sensitive regulation of HIF pathway under nonhypoxic conditions in pulmonary artery smooth muscle cells. Biol Chem 2004; 3850: 249-257.
114 Smadja DM, Laurendau I, Avignon C. et al. The angiopoietin pathway is modulated by PAR-1 activation of human endothelial progenitor cells. J Thromb Haemost 2006; 4: 2051-2058.
115 Bauer KA. New anticoagulants. Hematology Am Soc Hematol Educ Program. 2006: 450-456.
116 Hirsh J, O'Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin: current and future advances. Circulation 2007; 116: 552-560.
117 Brass LF, Vassallo RR, Belmonte E. et al. Structure and function of the human platelet thrombin receptor. Studies using monoclonal antibodies directed against a defined domain within the receptor N terminus. J Biol Chem 1992; 267: 13795-13798.
118 Cook JJ, Sitko GR, Bednar B. et al. An antibody against the exosite of the cloned thrombin receptor inhibits experimental arterial thrombosis in the African green monkey. Circulation 1995; 91: 2961-2971.
119 Covic L, Misra M, Badar J. et al. Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat Med 2002; 8: 1161-1165.
120 Leger AJ, Jacques SL, Badar J. et al. Blocking the protease-activated receptor 1-4 heterodimer in platelet mediated thrombosis. Circulation 2006; 113: 1244-1254.
121 Wu CC, Teng CM. Comparison of the effects of PAR1 antagonists, PAR4 antagonists, and their combinations on thrombin-induced human platelet activation. Eur J Pharmacol 2006; 546: 142-147.
122 Chackalamannil S. Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J Med Chem 2006; 49: 5389-5403.
123 Moliterno DJ, Becker RC, Jennings LK, Berman G, Yang B, Strony J, Veltri E. Harrington RA for the TRA-PCI Study Investigators. Results of a multinational randomized, double-blind, placebo-controlled study of a novel thrombin receptor antagonist (SCH 530348) in percutaneous coronary intervention. J Am Coll Cardiol 2007; 49 Abstr 2402-2409.
124 Martínez-González J, Badimon L. Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model. Eur J Clin Invest 1996; 26: 1023-1032.
125 Wojciack-Stothard B, Potempa S, Eichholtz T. et al. Rho and Rac but no Cdc42 regulate endothelial cell permeability. J Cell Sci 2001; 114: 1343-1355.
126 Ming XF, Viswambharan H, Barandier C. et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol 2002; 22: 8467-8477.
127 Kaneider NC, Egger P, Dunzendorfer S. et al. Reversal of thrombin-induced deactivation of CD39/ATPDase in endothelial cells by HMG-CoA reductase inhibition: effects on Rho-GTPase and adenosine nucleotide metabolism. Arterioscler Thromb Vasc Biol 2002; 22: 894-900.
128 Ming XF, Barandier C, Viswambharan H. et al. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation 2004; 110: 3708-3714.
129 Martínez-González J, Badimon L. Influence of statin use on endothelial function: from bench to clinics. Curr Pharm Des 2007; 13: 1771-1786.
130 Hale LP, Craver KT, Berrier AM. et al. Combination of fosinopril and pravastatin decreases platelets response to thrombin receptor agonist in monkeys. Artrioscler Thromb Vasc Biol 1998; 18: 1643-1646.
131 Serebruany VL, Miller M, Pokov AN. et al. Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study. Am J Cardiol 2006; 97: 1332-1336.
132 Kaneider NC, Egger P, Dunzendorfer S. et al. Rho-GTPase-dependent platelet-neutrophil interaction affected by HMG-CoA reductase inhibition with altered adenosine nucleotide release and function. Arterioscler Thromb Vasc Biol 2002; 22: 1029-1035.
133 Ferro D, Basili S, Alessandri C. et al. Inhibition of tissue-factor-mediated thrombin generation by simvastatin. Atherosclerosis 2000; 149: 111-116.
134 Eto M, Kozai T, Cosentino F. et al. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation 2002; 105: 1756-1759.
135 Yamakuchi M, Greer JJ, Cameron SJ. et al. HMGCoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. Circ Res 2005; 96: 1185-1192.
136 van Nieuw Amerongen GP, Vermeer MA, Nègre-Aminou P. et al. Simvastatin improves disturbed endothelial barrier function. Circulation 2000; 102: 2803-2809.
137 van Nieuw Amerongen GP, van Delft S, Vermeer MA. et al. Activation of RhoA by thrombin in endothelial hyperpermeability: Role of Rho Kinase and protein tyrosine kinases. Circ Res 2000; 87: 335-340.
138 Jacobson JR, Dudek SM, Birukov KG. et al. Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin. Am J Respir Cell Mol Biol 2004; 30: 662-670.