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
ISSN
0340-6245 (Print)
ISSN-L
0340-6245
Publication state
Published
Issued date
12/2004
Peer-reviewed
Oui
Volume
92
Number
6
Pages
1277-1283
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
Publication Status: ppublish
Publication Status: ppublish
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
Angioedema/blood, Cells, Cultured, Chlorine/metabolism, Coagulants/pharmacology, Complement C1 Inactivator Proteins/biosynthesis, Complement C1 Inactivator Proteins/pharmacology, Complement C1 Inhibitor Protein, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Endothelium, Vascular/cytology, Endothelium, Vascular/drug effects, Endothelium, Vascular/metabolism, Escherichia coli/metabolism, Escherichia coli Proteins/metabolism, Heterozygote, Humans, Kallikreins/antagonists & inhibitors, Kallikreins/blood, Kallikreins/metabolism, Kinetics, Metalloendopeptidases/metabolism, Protein Structure, Tertiary, Time Factors, Umbilical Veins/cytology
Pubmed
Web of science
Create date
25/01/2008 16:27
Last modification date
09/04/2024 7:14