Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor

Details

Serval ID
serval:BIB_321FB98C9A5D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor
Journal
Thrombosis and Haemostasis
Author(s)
Ravindran  S., Grys  T. E., Welch  R. A., Schapira  M., Patston  P. A.
ISSN
0340-6245 (Print)
Publication state
Published
Issued date
12/2004
Volume
92
Number
6
Pages
1277-83
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Dec
Abstract
Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with C1-inhibitor deficiency. Heterozygous individuals with <50% levels of active C1-inhibitor are susceptible to angioedema attacks indicating a critical need for C1-inhibitor to be present at maximum levels to prevent unwanted prekallikrein activation. Studies with purified proteins do not adequately explain this observation. Therefore to investigate why reduction of C1-inhibitor to levels seen in angioedema patients results in excessive kallikrein generation we examined the effect of endothelial cells on the inhibition of kallikrein by C1-inhibitor. Surprisingly, it was found that a C1-inhibitor concentration of greater than 1 microM was needed to inhibit 3 nM kallikrein. We propose that this apparent protection from inhibition was mediated by kallikrein binding to the cells via the heavy chain in a high molecular weight kininogen and zinc independent manner. Protection of kallikrein from inhibition was not observed when C1-inhibitor truncated in the amino-terminal domain by the StcE metalloproteinase was used, which suggests a novel function for this unique domain. The requirement for high concentrations of C1-inhibitor to fully inhibit kallikrein is consistent with the fact that reduced levels of C1-inhibitor result in the kallikrein activation seen in angioedema.
Keywords
Angioneurotic Edema/blood Cells, Cultured Chlorine/metabolism Coagulants/pharmacology Complement C1 Inactivator Proteins/*biosynthesis/*pharmacology Complement C1 Inhibitor Protein Dose-Response Relationship, Drug Electrophoresis, Polyacrylamide Gel Endothelium, Vascular/cytology/*drug effects/*metabolism Escherichia coli/metabolism Escherichia coli Proteins/metabolism Heterozygote Humans Kallikreins/*antagonists & inhibitors/*blood/metabolism Kinetics Metalloendopeptidases/metabolism Protein Structure, Tertiary Time Factors Umbilical Veins/cytology
Pubmed
Web of science
Create date
25/01/2008 15:27
Last modification date
20/08/2019 13:17
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