Inhibition of plasma kallikrein by CI-inhibitor: Role of endothelial cells and the amino-terminal domain of CI-inhibitor

Sriram Ravindran, Thomas E. Grys, Rodney A. Welch, Marc Schapira, Philip A. Patston

Research output: Contribution to journalArticle

20 Scopus citations

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 μM 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.

Original languageEnglish (US)
Pages (from-to)1277-1283
Number of pages7
JournalThrombosis and Haemostasis
Volume92
Issue number6
DOIs
StatePublished - Dec 1 2004

Keywords

  • Coagulation inhibitors
  • Contact phase
  • Endothelial cells
  • Proteases/inhibitors

ASJC Scopus subject areas

  • Hematology

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