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C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema.
Biochim Biophys Acta 2015; 1850(6):1336-42BB

Abstract

BACKGROUND

The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients.

METHODS

C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method.

RESULTS

C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo.

CONCLUSION

Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system.

GENERAL SIGNIFICANCE

The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS.

Authors+Show Affiliations

University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark. Electronic address: daniel@elenius.eu.University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark.University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark.University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark.University of Southern Denmark, Institute of Molecular Medicine, Department of Cancer and Inflammation Research, J.B. Winsløws Vej 21, 5000 Odense C, Denmark.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25800206

Citation

Madsen, Daniel Elenius, et al. "C1-inhibitor Polymers Activate the FXII-dependent Kallikrein-kinin System: Implication for a Role in Hereditary Angioedema." Biochimica Et Biophysica Acta, vol. 1850, no. 6, 2015, pp. 1336-42.
Madsen DE, Sidelmann JJ, Biltoft D, et al. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema. Biochim Biophys Acta. 2015;1850(6):1336-42.
Madsen, D. E., Sidelmann, J. J., Biltoft, D., Gram, J., & Hansen, S. (2015). C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema. Biochimica Et Biophysica Acta, 1850(6), pp. 1336-42. doi:10.1016/j.bbagen.2015.03.005.
Madsen DE, et al. C1-inhibitor Polymers Activate the FXII-dependent Kallikrein-kinin System: Implication for a Role in Hereditary Angioedema. Biochim Biophys Acta. 2015;1850(6):1336-42. PubMed PMID: 25800206.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema. AU - Madsen,Daniel Elenius, AU - Sidelmann,Johannes Jakobsen, AU - Biltoft,Daniel, AU - Gram,Jørgen, AU - Hansen,Soren, Y1 - 2015/03/20/ PY - 2014/10/17/received PY - 2015/02/12/revised PY - 2015/03/13/accepted PY - 2015/3/25/entrez PY - 2015/3/25/pubmed PY - 2015/9/1/medline KW - Coagulation factor XII KW - Complement C1 esterase inhibitor KW - Hereditary angioedema KW - Kallikrein-kinin system KW - Polymerization KW - Serpinopathy SP - 1336 EP - 42 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1850 IS - 6 N2 - BACKGROUND: The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. METHODS: C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method. RESULTS: C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo. CONCLUSION: Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system. GENERAL SIGNIFICANCE: The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/25800206/C1_inhibitor_polymers_activate_the_FXII_dependent_kallikrein_kinin_system:_Implication_for_a_role_in_hereditary_angioedema_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-4165(15)00085-9 DB - PRIME DP - Unbound Medicine ER -