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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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Volume 394, Issue 9


Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents

Jenny Björkqvist
  • Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Bernd Lecher / Coen Maas
  • Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thomas Renné
  • Corresponding author
  • Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-05-01 | DOI: https://doi.org/10.1515/hsz-2013-0144


Contact to polyanions induces autoactivation of the serine protease factor XII that triggers the kallikrei-kinin system. Recent studies indicate that polysaccharide-induced autoactivation of factor XII has a role in allergy-related vascular leakage, and angioedema. Here, we characterize in vivo effects of the synthetic polysaccharide dextran sulfate in human plasma and in rodent models. Minute amounts of high-molecular-weight dextran sulfate-initiated factor XII-autoactivation and triggered formation of the inflammatory mediator bradykinin via plasma kallikrein-mediated cleavage of high-molecular-weight kininogen. High-molecular-weight kininogen fragments, containing the HKH20 sequence in domain D5H, blocked dextran sulfate-initiated bradykinin-generation by depleting plasma Zn2+ ions. Topical application of high molecular weight dextran sulfate increased leakage in murine skin microvessels, in a bradykinin-dependent manner. Intravital laser scanning microscopy showed a greater than two-fold elevated and accelerated fluid extravasation in C1 esterase inhibitor deficient mice that lack the major inhibitor of factor XII, compared to wild-type controls. Intra-arterial infusion of dextran sulfate induced a rapid transient drop in arterial blood pressure in rats and preinjection of kinin B2 receptor antagonists or HKH20 peptide blunted dextran sulfate-triggered hypotensive reactions. The data characterize dextran sulfate as a potent in vivo activator of factor XII with implications for bradykinin-mediated vascular permeability and blood pressure control.

Keywords: angioedema; bradykinin; coagulation; inflammation; kallikrein-kinin system


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About the article

Corresponding author: Thomas Renné, MD, PhD, Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden

Received: 2012-10-31

Accepted: 2013-04-24

Published Online: 2013-05-01

Published in Print: 2013-09-01

Citation Information: Biological Chemistry, Volume 394, Issue 9, Pages 1195–1204, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2013-0144.

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