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J. Biol. Chem., Vol. 277, Issue 9, 7529-7539, March 1, 2002
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From the Departments of Type 1 plasminogen activator inhibitor (PAI-1),
the primary inhibitor of tissue-type plasminogen activator (t-PA), is
found in plasma and platelets. PAI-1 circulates in complex with
vitronectin (Vn), an interaction that stabilizes PAI-1 in its active
conform. In this study, we examined the binding of platelet-derived Vn and PAI-1 to the surface of isolated platelets. Flow cytometry indicate
that, like P-selectin, PAI-1, and Vn are found on the surface of
thrombin- or calcium ionophore-activated platelets and platelet
microparticles. The binding of PAI-1 to the activated platelet surface
is Vn-dependent. Vn mediates the binding of PAI-1 to
platelet surfaces through a high affinity (Kd of 80 nM) binding interaction with the NH2 terminus
of vimentin, and this Vn-binding domain is expressed on the surface of
activated platelets and platelet microparticles. Immunological and
functional assays indicate that only
Vimentin Exposed on Activated Platelets and Platelet
Microparticles Localizes Vitronectin and Plasminogen Activator
Inhibitor Complexes on Their Surface*
§¶,§,§,§,§,
, and Pathology and Molecular
Medicine, and § Medicine, McMaster University and the
Hamilton Civic Hospitals Research Centre, Hamilton, Ontario L8V 1C3,
Canada, Pfizer Pharmaceuticals, Montreal, Quebec H9J 2M5,
Canada, and the ** Ottawa Heart Institute, University of
Ottawa, Ottawa, Ontario K1Y 4W7, Canada
5% of the total PAI-1 in
platelet releasates is functionally active, and it co-precipitates with
Vn, and the vimentin-enriched cytoskeleton fraction of activated
platelet debris. The remaining platelet PAI-1 is inactive, and does not associate with the cytoskeletal debris of activated platelets. Confocal
microscopic analysis of platelet-rich plasma clots confirm the
co-localization of PAI-1 with Vn and vimentin on the surface of
activated platelets, and platelet microparticles. These findings suggest that platelet vimentin may regulate fibrinolysis in plasma and
thrombi by binding platelet-derived Vn·PAI-1 complexes.
*
This work was supported by an operating grant from the
Canadian Institutes of Health Research (to T. J. P), Career
Investigator Awards from the Heart and Stroke Foundation of Canada (to
T. J. P. and J. I. W.), and a grant from the
Medical Research Council of Canada/University-Industry (Pfizer
Pharmaceuticals) (to T. J. P., R. M., and R. D.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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