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J. Biol. Chem., Vol. 277, Issue 36, 32677-32682, September 6, 2002
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From the The adhesive glycoprotein vitronectin (VN)
forms a function-stabilizing complex with plasminogen activator
inhibitor-1 (PAI-1), the major fibrinolysis inhibitor in both plasma
and vessel wall connective tissue. VN also interacts with two-chain
high molecular weight kininogen (HKa), particularly its
His-Gly-Lys-rich domain 5, and both HKa and PAI-1 are antiadhesive
factors that have been shown to compete for binding to VN. In this
study the influence of HKa and domain 5 on the antifibrinolytic
function of PAI-1 was investigated. In a purified system, HKa and
particularly domain 5 inhibited the binding of PAI-1 to VN and promoted
PAI-1 displacement from both isolated VN as well as subendothelial
extracellular matrix-associated VN. The sequence
Gly486-Lys502 of HKa domain 5 was
identified as responsible for this inhibition. Although having no
direct effect on PAI-1 activity itself, HKa domain 5 or the
peptide Gly486-Lys502 markedly destabilized the
VN·PAI-1 complex interaction, resulting in a significant
reduction of PAI-1 inhibitory function on plasminogen activators,
resembling the effect of VN antibodies that prevent stabilization of
PAI-1. Furthermore, high affinity fibrin binding of PAI-1 in the
presence of VN as well as the VN-dependent fibrin clot
stabilization by the inhibitor were abrogated in the presence of the
kininogen forms mentioned. Taken together, our data indicate that the
peptide Gly486-Lys502 derived from domain 5 of
HKa serves to interfere with PAI-1 function. Based on these
observations potential low molecular weight PAI-1 inhibitors could be
designed for the use in therapeutic interventions against
thromboembolic complications.
A Novel Antithrombotic Role for High Molecular Weight Kininogen
as Inhibitor of Plasminogen Activator Inhibitor-1 Function*
§¶,
,,, and
Institute for Biochemistry,
§ Third Department of Internal Medicine, Justus Liebig
University, Giessen D-35392, Germany, and the Sol Sherry
Thrombosis Research Center, Temple University School of Medicine,
Philadelphia, Pennsylvania 19140
*
This work was supported in part by a grant from the Novartis
Foundation for Therapeutical Research, Nürnberg, Germany (to K. T. P. and T. C.)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.
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