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

Summary

Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with C1inhibitor 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 C1inhibitor 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.

Keywords

Coagulation inhibitors - proteases/inhibitors - endothelial cells - contact phase

• References

• 1 Carugati A, Pappalardo E, Zingale LC. et al. C1-inhibitor deficiency and angioedema. Mol Immunol 2001; 38: 161-73.
• 2 Cicardi M, Igarashi T, Rosen FS. et al. Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest 1987; 79: 698-702.
• 3 Kramer J, Rosen FS, Colten HR. et al. Transinhibition of C1 inhibitor synthesis in type I hereditary angioneurotic edema. J Clin Invest 1993; 91: 1258-62.
• 4 Pappalardo E, Zingale LC, Cicardi M. C1 inhibitor gene expression in patients with hereditary angioedema: Quantitative evaluation by means of real-time RT-PCR. J Allergy Clin Immunol 2004; 114: 638-44.
• 5 Pappalardo E, Zingale LC, Terlizzi A. et al. Mechanisms of C1-inhibitor deficiency. Immunobiology 2002; 205: 542-51.
• 6 Davis 3^rd AE. The pathogenesis of hereditary angioedema. Transfusion Apher Sci 2003; 29: 195-203.
• 7 Motta G, Rojkjaer R, Hasan AAK. et al. High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: A novel mechanism for contact activation. Blood 1998; 91: 516-28.
• 8 Schmaier AH, Røjkjær R, Shariat-Madar Z. Activation of the plasma kallikrein/kinin system on cells: A revised hypothesis. Thromb Haemost 1999; 82: 226-33.
• 9 Schmaier AH. The plasma kallikrein-kinin system counterbalances the renin-angiotensin system. J Clin Invest 2002; 109: 1007-9.
• 10 Shariat-Madar Z, Mahdi F, Schmaier AH. Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem 2002; 277: 17962-9.
• 11 Moreira CR, Schmaier AH, Mahdi F. et al. Identification of prolylcarboxypeptidase as the cell matrix-associated prekallikrein activator. FEBS Lett 2002; 523: 167-70.
• 12 Joseph K, Ghebrehiwet B, Kaplan AP. Activation of the kinin-forming cascade on the surface of endothelial cells. Biol Chem 2001; 382: 71-5.
• 13 Joseph K, Tholanikunnel BG, Kaplan AP. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci USA 2002; 99: 896-900.
• 14 Mahdi F, Shariat-Madar Z, Figueroa CD. et al. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 2002; 99: 3585-96.
• 15 Rojkjaer R, Hasan AA, Motta G. et al. Factor XII does not initiate prekallikrein activation on endothelial cells. Thromb Haemost 1998; 80: 74-81.
• 16 Schapira M, Scott CF, Colman RW. Contribution of plasma protease inhibitors to the inactivation of kallikrein in plasma. J Clin Invest 1982; 69: 462-8.
• 17 van der Graaf F, Koedam JA, Bouma BN. Inactivation of kallikrein in human plasma. J Clin Invest 1983; 71: 149-58.
• 18 Harpel PC, Lewin MF, Kaplan AP. Distribution of plasma kallikrein between C1 inactivator and α₂-macroglobulin in plasma utilizing a new assay for α₂-macroglobulinkallikrein complexes. J Biol Chem 1985; 260: 4257-63.
• 19 van der Graaf F, Koedam JA, Griffin JH. et al. Interaction of human plasma kallikrein and its light chain with C1 inhibitor. Biochemistry 1983; 22: 4860-6.
• 20 Wachtfogel Y, Harpel PC, Edmunds Jr H. et al. Formation of C1s-C1-inhibitor, kallikrein-C1-inhibitor, and plasmin-α2-plasmin-inhibitor complexes during cardiopulmonary bypass. Blood 1989; 73: 468-71.
• 21 Veloso D, Colman RW. Western blot analyses of prekallikrein and its activation products in human plasma. Thromb Haemost 1991; 65: 382-8.
• 22 Brown EW, Ravindran S, Patston PA. The reaction between plasmin and C1-inhibitor results in plasmin inhibition by the serpin mechanism. Blood Coag Fibrinolys 2002; 13: 711-4.
• 23 Lathem WW, Grys TE, Witowski SE. et al. StcE, a metalloprotease secreted by Escherichia coli O157:H7, specifically cleaves C1 esterase inhibitor. Mol Microbiol 2002; 45: 277-88.
• 24 Patston PA, Gettins P, Beechem J. et al. Mechanism of serpin action: evidence that C1 inhibitor functions as a suicide substrate. Biochemistry 1991; 30: 8876-82.
• 25 Sulikowski T, Bauer BA, Patston PA. α₁-Proteinase inhibitor mutants with specificity for plasma kallikrein and C1s but not C1. Protein Sci 2002; 11: 2230-6.
• 26 van der Graaf F, Tans G, Bouma BN. et al. Isolation and functional properties of the heavy and light chains of human plasma kallikrein. J Biol Chem 1982; 257: 14300-5.
• 27 Schousboe I. Binding of activated Factor XII to endothelial cells affects its inactivation by the C1-esterase inhibitor. Eur J Biochem 2003; 270: 111-8.
• 28 Lathem WW, Bergsbaken T, Welch RA. Potentiation of C1 esterase inhibitor by StcE, a metalloprotease secreted by Escherichia coli O157:H7. J Exp Med 2004; 199: 1077-87.
• 29 Bock SC, Skriver K, Nielsen E. et al. Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization. Biochemistry 1986; 25: 4292-301.
• 30 Perkins SJ, Smith KF, Amatayakul S. et al. Two-domain structure of the native and reactive centre cleaved forms of C1 inhibitor of human complement by neutron scattering. J Mol Biol 1990; 214: 751-63.
• 31 Liu D, Cai S, Gu X. et al. C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide. J Immunol 2003; 171: 2594-601.
• 32 Liu D, Gu X, Scafidi J. et al. N-linked glycosylation is required for C1 inhibitor-mediated protection from endotoxin shock in mice. Infect Immun 2004; 72: 1946-55.
• 33 Han ED, MacFarlane RC, Mulligan AN. et al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109: 1057-63.
• 34 Cugno M, Nussberger J, Cicardi M. et al. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003; 03: 311-7.