Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents
| Autor: | Thomas Renné, Coen Maas, Bernd Lecher, Jenny Björkqvist |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Anions
Male Clinical Biochemistry Bradykinin Inflammation 030204 cardiovascular system & hematology Pharmacology Factor XIIa Biochemistry Capillary Permeability 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine In vivo medicine Animals Humans Rats Wistar Molecular Biology 030304 developmental biology 0303 health sciences Factor XII Kininogen Dextran Sulfate Kinin Extravasation 3. Good health Rats Mice Inbred C57BL Zinc Dextran chemistry Kallikreins medicine.symptom Hypotension circulatory and respiratory physiology |
| Zdroj: | Biological chemistry. 394(9) |
| ISSN: | 1437-4315 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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