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Human high molecular weight kininogen binds to human umbilical vein
endothelial cells via its heavy and light chains
SR Reddigari, P Kuna, G Miragliotta, Y Shibayama, K Nishikawa and AP Kaplan
Department of Medicine, State University of New York, Stony Brook 11794.
High molecular weight kininogen (HK) is a multifunctional plasma
glycoprotein that occupies a critical position in pathways that link
inflammation and coagulation. Excision of the vasoactive peptide bradykinin
by plasma kallikrein results in kinin-free HK that consists of a 65-Kd
N-terminal heavy chain (HK-HC) linked to the C-terminal 45- Kd light chain
(HK-LC) by a disulfide bridge. HK-HC is an inhibitor of SH-proteases and
HK-LC contains the binding sites for coagulation cofactors prekallikrein
and factor XI. HK has previously been shown to bind specifically to human
umbilical vein endothelial cells (HUVEC) in a zinc(2+)-dependent manner by
a single class of high-affinity binding sites. We have further
characterized that interaction in order to determine the cell-binding
regions of HK. Competition binding experiments have indicated that either
HK-LC or HK-HC was able to inhibit the binding of labeled HK with a 50%
inhibitory concentration (IC50) of 77 nmol/L and 89 nmol/L, respectively.
Cleaved two-chain HK (HKa) had an IC50 of 73 nmol/L, whereas uncleaved HK
had an IC50 of 335 nmol/L. Direct binding experiments have indicated that
HUVEC bind both purified [125I]HK-HC and [125I]HK-LC in a
zinc(2+)-dependent manner and that HK-LC did not displace bound HK-HC. The
light chain of low molecular weight kininogen or prekallikrein-binding
region of HK did not inhibit the binding of HK to HUVEC. Our results,
therefore, indicate that (1) HK is capable of binding to endothelial cells
via both heavy and light chain moieties, (2) HKa has a higher affinity to
HUVEC, and (3) purified heavy and light chains are capable of directly
binding to HUVEC. The data are consistent with the presence of a single
high-affinity site for HK on endothelial cells within which are subsites
that bind to heavy and light chains.
Volume 81,
Issue 5,
pp. 1306-1311,
03/01/1993
Copyright © 1993 by The American Society of Hematology
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