This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stoop, A. A. Articles by Pannekoek, H. Search for Related Content PubMed PubMed Citation Articles by Stoop, A. A. Articles by Pannekoek, H. Related Collections Pathophysiology Fibrinolysis Smooth muscle proliferation and differentiation Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1143.)
© 2000 American Heart Association, Inc.

Thrombosis

Colocalization of Thrombin, PAI-1, and Vitronectin in the Atherosclerotic Vessel Wall

A Potential Regulatory Mechanism of Thrombin Activity by PAI-1/Vitronectin Complexes

A. Allart Stoop; Florea Lupu; Hans Pannekoek

From the Department of Biochemistry (A.A.-S., H.P.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and the Vascular Biology Laboratory (F.L.), Weston Centre for Experimental Research, Thrombosis Research Institute, London, UK.

Correspondence to A. Allart-Stoop, Academic Medical Center, Department of Biochemistry (K1-161), Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands. E-mail a.a.stoop{at}amc.uva.nl

Abstract—The serine protease thrombin is a mitogen for vascular smooth muscle cells. To that end, thrombin cleaves the surface-exposed, protease-activated receptor type 1 (PAR-1), resulting in signal transduction and ultimately, proliferation of these cells. Regulation of thrombin activity in the human atherosclerotic vessel wall has not been studied in great detail, conceivably because the traditional plasma thrombin inhibitor, anti–thrombin III, is not encountered at this location. By using immunofluorescence confocal microscopy, we demonstrate that the antigens of thrombin, plasminogen activator inhibitor 1 (PAI-1), and vitronectin (Vn) colocalize in human neointimal atherosclerotic arterial tissue. Furthermore, it is shown by in situ reverse zymography that these specimens harbor the active form of PAI-1, which is the only configuration of PAI-1 capable of complexing with Vn and inhibiting serine proteases, eg, thrombin. Two different criteria were used to establish that neointimal atherosclerotic material contains active -thrombin, namely, its ability to bind to the thrombin inhibitor hirudin and to convert the thrombin-specific chromogenic substrate S2238. The latter activity could be fully prevented by preincubation with the thrombin-specific inhibitor, phenyl-prolyl-arginyl-chloromethyl ketone. The thrombin concentration measured by conversion of the chromogenic substrate was 7 to 12 nmol/L in the vascular specimens studied. This concentration range suffices to activate the PAR-1 receptor on vascular smooth muscle cells and to cause neointimal proliferation. It is concluded that the human atherosclerotic arterial vessel wall provides conditions that favor a regulatory mechanism of thrombin activity by PAI-1/Vn complexes.

Key Words: atherosclerosis • smooth muscle cells • thrombin • PAI-1 • vitronectin

This article has been cited by other articles:

				C. P. Vicente, L. He, and D. M. Tollefsen Accelerated atherogenesis and neointima formation in heparin cofactor II deficient mice Blood, December 15, 2007; 110(13): 4261 - 4267. [Abstract] [Full Text] [PDF]

				D. M. Tollefsen Heparin Cofactor II Modulates the Response to Vascular Injury Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 454 - 460. [Abstract] [Full Text] [PDF]

				K. H. Minor, C. R. Schar, G. E. Blouse, J. D. Shore, D. A. Lawrence, P. Schuck, and C. B. Peterson A Mechanism for Assembly of Complexes of Vitronectin and Plasminogen Activator Inhibitor-1 from Sedimentation Velocity Analysis J. Biol. Chem., August 5, 2005; 280(31): 28711 - 28720. [Abstract] [Full Text] [PDF]

				H. Ekmekci, O. B. Ekmekci, H. Sonmez, Z. Ozturk, N. Domanic, and E. Kokoglu Evaluation of Fibronectin, Vitronectin, and Leptin Levels in Coronary Artery Disease: Impacts on Thrombosis and Thrombolysis Clinical and Applied Thrombosis/Hemostasis, January 1, 2005; 11(1): 63 - 70. [Abstract] [PDF]

				D. M. Tollefsen Does Heparin Cofactor II Modulate Atherosclerosis and Restenosis? Circulation, June 8, 2004; 109(22): 2682 - 2684. [Full Text] [PDF]

				R. Colognato, J. R. Slupsky, M. Jendrach, L. Burysek, T. Syrovets, and T. Simmet Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells Blood, October 1, 2003; 102(7): 2645 - 2652. [Abstract] [Full Text] [PDF]

				E. Dai, H. Guan, L. Liu, S. Little, G. McFadden, S. Vaziri, H. Cao, I. A. Ivanova, L. Bocksch, and A. Lucas Serp-1, a Viral Anti-inflammatory Serpin, Regulates Cellular Serine Proteinase and Serpin Responses to Vascular Injury J. Biol. Chem., May 9, 2003; 278(20): 18563 - 18572. [Abstract] [Full Text] [PDF]

				A. T. Askari, M.-L. Brennan, X. Zhou, J. Drinko, A. Morehead, J. D. Thomas, E. J. Topol, S. L. Hazen, and M. S. Penn Myeloperoxidase and Plasminogen Activator Inhibitor 1 Play a Central Role in Ventricular Remodeling after Myocardial Infarction J. Exp. Med., March 3, 2003; 197(5): 615 - 624. [Abstract] [Full Text] [PDF]

				M.-C. Bouton, B. Richard, P. Rossignol, M. Philippe, M.-C. Guillin, J.-B. Michel, and M. Jandrot-Perrus The Serpin Protease-Nexin 1 Is Present in Rat Aortic Smooth Muscle Cells and Is Upregulated in L-NAME Hypertensive Rats Arterioscler Thromb Vasc Biol, January 13, 2003; 23(1): 142 - 147. [Abstract] [Full Text] [PDF]

				S. Konstantinides, K. Schafer, and D. J. Loskutoff Do PAI-1 and Vitronectin Promote or Inhibit Neointima Formation?: The Exact Role of the Fibrinolytic System in Vascular Remodeling Remains Uncertain Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1943 - 1945. [Full Text] [PDF]

				V. de Waard, E. K. Arkenbout, P. Carmeliet, V. Lindner, and H. Pannekoek Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1978 - 1983. [Abstract] [Full Text] [PDF]

				K. H. Minor and C. B. Peterson Plasminogen Activator Inhibitor Type 1 Promotes the Self-association of Vitronectin into Complexes Exhibiting Altered Incorporation into the Extracellular Matrix J. Biol. Chem., March 15, 2002; 277(12): 10337 - 10345. [Abstract] [Full Text] [PDF]

				T. J. Podor, S. Campbell, P. Chindemi, D. M. Foulon, D. H. Farrell, P. D. Walton, J. I. Weitz, and C. B. Peterson Incorporation of Vitronectin into Fibrin Clots. EVIDENCE FOR A BINDING INTERACTION BETWEEN VITRONECTIN AND gamma A/gamma ' FIBRINOGEN J. Biol. Chem., February 22, 2002; 277(9): 7520 - 7528. [Abstract] [Full Text] [PDF]

				C. Patterson, G. A. Stouffer, N. Madamanchi, and M. S. Runge New Tricks for Old Dogs : Nonthrombotic Effects of Thrombin in Vessel Wall Biology Circ. Res., May 25, 2001; 88(10): 987 - 997. [Abstract] [Full Text] [PDF]