RSS-Feed abonnieren
DOI: 10.1055/s-0037-1614051
Factor Xa Acts as a PDGF-Independent Mitogen in Human Vascular Smooth Muscle Cells
This study was supported by the Verbund für Klinische Forschung of the Friedrich-Schiller-Universität Jena (FS 5, Projekt 4) and by the Deutsche Forschungsgemeinschaft (Schr 194/10-3). The authors wish to thank Dr. S. Kunitada (Daiichi Pharmaceuticals, Tokyo, Japan) for the generous supply with DX-9065a, Dr. J. Stürzebecher and Dr. Dagmar Prasa for their support in measuring thrombin generation. The authors are also grateful to Marlies Laube and Christine Machunsky for competent technical assistance and to Erika Lohmann for secretarial help.Publikationsverlauf
Received
22. Februar 2000
Accepted after resubmission
17. April 2000
Publikationsdatum:
14. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200003/lookinside/thumbnails/10-1055s-0037-1614051-1.jpg)
Summary
This study investigates the mitogenic effect of the coagulation factor Xa in smooth muscle cells (SMC) from human saphenous vein and the procoagulant activity of these cells. Factor Xa elicited a concentrationdependent increase in [3H]thymidine incorporation. This mitogenic effect of factor Xa was inhibited by DX-9065a and BABCH, indicating the requirement of proteolytic activity of the enzyme. Factor Xa activated the MAP kinases ERK1/2 concentration-and time-dependently. PDGF-neutralizing antibodies neither inhibited the increase in [3H]thymidine incorporation nor ERK-1/2 phosphorylation in factor Xa-stimulated cells, suggesting that factor Xa-induced signaling and mitogenic activity in human venous SMC are independent of PDGF. Exposure of SMC to recalcified plasma resulted in a significant thrombin generation which was inhibited by anti-tissue factor antibody, tissue factor pathway inhibitor, inactivated factor VIIa and DX-9065a. These data indicate that interaction of SMC with the clotting system may contribute to venous graft disease, i.e. thrombus formation and intimal hyperplasia.
-
References
- 1 Solymoss BC, Leung TK, Pelletier LC, Campeau L. Pathologic changes in coronary artery saphenous vein grafts and related etiologic factors. Cardiovasc Clin 1991; 21: 45-65.
- 2 Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996; 28: 616-26.
- 3 Cox JL, Chiasson DA, Gotlieb AI. Stranger in a strange land: the pathogenesis of saphenous vein graft stenosis with emphasis on structural and functional differences between veins and arteries. Prog Cardiovasc Dis 1991; 34: 45-68.
- 4 Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease. Pathogenesis, predisposition, and prevention. Circulation 1998; 97: 916-31.
- 5 Angelini GD, Passani SL, Breckenridge IM, Newby AC. Nature and pressure dependence of damage induced by distension of human saphenous vein coronary artery bypass grafts. Cardiovasc Res 1987; 21: 902-7.
- 6 Roubos N, Rosenfeldt FL, Richards SM, Conyers RAJ, Davis BB. Improved preservation of saphenous vein grafts by the use of glyceryl trinitrate-verapamil solution during harvesting. Circulation 1995; 92 (suppl. II) II-31-6.
- 7 Carmeliet P, Collen D. Molecules in focus. Tissue factor. Int J Biochem Cell Biol 1998; 30: 661-7.
- 8 Taubman MB, Marmur JD, Rosenfield C-L, Guha A, Nichtberger S, Nemerson Y. Agonist-mediated tissue factor expression in cultured vascular smooth muscle cells. J Clin Invest 1993; 91: 547-52.
- 9 Hatakeyama K, Asada Y, Marutsuka K, Sato Y, Kamikubo Y, Sumiyoshi A. Localization and activity of tissue factor in human aortic atherosclerotic lesions. Atherosclerosis 1997; 133: 213-9.
- 10 Kaiser B, Hoppensteadt DH, Fareed J. Recombinant TFPI and variants: potential implications in the treatment of cardiovascular disorders. Exp Opin Invest Drugs 1998; 07: 1121-37.
- 11 Amano J, Suzuki A, Sunamori M, Tsukada T, Numano F. Cytokinetic study of aortocoronary bypass vein grafts in place for less than six months. Am J Cardiol 1991; 67: 1234-6.
- 12 Bretschneider E, Wittpoth M, Weber A-A, Glusa E, Schrör K. Activation of NFκB is essential but not sufficient to stimulate mitogenesis of vascular smooth muscle cells. Biochem Biophys Res Commun 1997; 235: 365-8.
- 13 Yang Z, Ruschitzka F, Rabelink TJ, Noll G, Julmy F, Joch H, Gafner V, Aleksic I, Althaus U, Lüscher TF. Different effects of thrombin receptor activation on endothelium and smooth muscle cells of human coronary bypass vessels. Circulation 1997; 95: 1870-6.
- 14 Gasic GP, Arenas CP, Gasic TB, Gasic GJ. Coagulation factors X, Xa, and protein S as potent mitogens of cultured aortic smooth muscle cells. Proc Natl Acad Sci USA 1992; 89: 2317-20.
- 15 Ko FN, Yang YC, Huang SC, Ou JT. Coagulation factor Xa stimulates platelet-derived growth factor release and mitogenesis in cultured vascular smooth muscle cells of rat. J Clin Invest 1996; 98: 1493-501.
- 16 Nicholson AC, Nachman RL, Altieri DC, Summers BD, Ruf W, Edgington TS, Hajjar DP. Effector cell protease receptor-1 is a vascular receptor for coagulation factor Xa. J Biol Chem 1996; 271: 28407-13.
- 17 Herbert J-M, Bono F, Hérault J-P, Avril C, Dol F, Mares A-M, Schaeffer P. Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo. J Clin Invest 1998; 101: 993-1000.
- 18 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54.
- 19 Stürzebecher J, Stürzebecher U, Vieweg H, Wagner G, Hauptmann J, Markwardt F. Synthetic inhibitors of bovine factor Xa and thrombin. Comparison of their anticoagulant efficiency. Thromb Res 1989; 54: 245-52.
- 20 Hara T, Yokoyama A, Ishihara H, Yokoyama Y, Nagahara T, Iwamoto M. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Thromb Haemost 1994; 71: 314-9.
- 21 Jang Y, Guzman LA, Lincoff AM, Gottsauner-Wolf M, Forudi F, Hart ChE, Courtman DW, Ezban M, Ellis SG, Topol EJ. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation 1995; 92: 3041-50.
- 22 Oltrona L, Speidel ChM, Recchia D, Wickline SA, Eisenberg PR, Abendschein DR. Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after balloon-induced arterial injury in minipigs. Circulation 1997; 96: 646-52.
- 23 Harker LA, Hanson SR, Wilcox JN, Kelly AB. Antithrombotic and antilesion benefits without hemorrhagic risks by inhibiting tissue factor pathway. Haemostasis 1996; 26 (Suppl. 01) 76-82.
- 24 Schwartz RS, Holder DJ, Holmes DR, Veinot JP, Camrud AR, Jorgenson MA, Johnson RG. Neointimal thickening after severe coronary artery injury is limited by short-term administration of a factor Xa inhibitor. Circulation 1996; 93: 1542-8.
- 25 Bauters C, Lablanche JM, McFadden EP, Hamon M, Bertrand ME. Relation of coronary angioscopic findings at coronary angioplasty to angiographic restenosis. Circulation 1995; 92: 2473-9.
- 26 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
- 27 Prager NA, Abendschein DR, McKenzie CR, Eisenberg PR. Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots. Circulation 1995; 92: 962-7.
- 28 Furie B, Furie BC. The molecular basis of blood coagulation. Cell 1988; 53: 505-18.
- 29 Altieri DC. Xa receptor EPR-1. FASEB J 1995; 09: 860-5.
- 30 Herbert J-M, Bono F, Hérault J-P, Michaux C, Nestor A-L, Guillemot J-C, Altieri D, Schaeffer P. Activation of endothelial cells by factor Xa reveals a new mode of activation of the PAR-2 receptor. Thromb Haemost 1999; 82 (suppl.) 693 [abstract].
- 31 Camerer E, Rottingen J-A, Gjernes E, Larsen K, Skartlien AH, Iversen J-G, Prydz H. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
- 32 Molino M, Raghunath PN, Kuo A, Ahuja M, Hoxie JA, Brass LF, Barnathan ES. Differential expression of functional protease-activated receptor-2 (PAR-2) in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1998; 18: 825-32.