© 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
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
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