Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor.
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.
Ravindran
Sriram
S
Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Grys
Thomas E
TE
Welch
Rodney A
RA
Schapira
Marc
M
Patston
Philip A
PA
D000799:Angioedema / Q000097:blood; D002478:Cells, Cultured; D002713:Chlorine / Q000378:metabolism; D003029:Coagulants / Q000494:pharmacology; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis* / Q000494:pharmacology*; D050718:Complement C1 Inhibitor Protein; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000378:metabolism; D007700:Kinetics; D008666:Metalloendopeptidases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
D003029:Coagulants; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D029968:Escherichia coli Proteins; D002713:Chlorine; D007610:Kallikreins; D008666:Metalloendopeptidases; C465555:StcE protein, E coli