Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents
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Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents. / Björkqvist, Jenny; Lecher, Bernd; Maas, Coen; Renné, Thomas.
in: BIOL CHEM, Jahrgang 394, Nr. 9, 01.09.2013, S. 1195-204.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents
AU - Björkqvist, Jenny
AU - Lecher, Bernd
AU - Maas, Coen
AU - Renné, Thomas
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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.
AB - 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.
KW - Animals
KW - Anions
KW - Bradykinin
KW - Capillary Permeability
KW - Dextran Sulfate
KW - Factor XII
KW - Factor XIIa
KW - Humans
KW - Hypotension
KW - Kallikreins
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Rats
KW - Rats, Wistar
KW - Zinc
U2 - 10.1515/hsz-2013-0144
DO - 10.1515/hsz-2013-0144
M3 - SCORING: Journal article
C2 - 23640941
VL - 394
SP - 1195
EP - 1204
JO - BIOL CHEM
JF - BIOL CHEM
SN - 1431-6730
IS - 9
ER -