Marion Gröger, Waltraud Pasteiner, George Ignatyev, Ulrich Matt, Sylvia Knapp, Alena Atrasheuskaya, Eugenij Bukin, Peter Friedl, Daniela Zinkl, Renate Hofer-Warbinek, Kai Zacharowski, Peter Petzelbauer, Sonja Reingruber
- Loss of vascular barrier function causes leak of fluid and proteins into tissues, extensive leak leads to shock and death. Barriers are largely formed by endothelial cell-cell contacts built up by VE-cadherin and are under the control of RhoGTPases. Here we show that a natural plasmin digest product of fibrin, peptide Bß15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. The ability of Bß15-42 to preserve endothelial barriers is confirmed in rats i.v.-injected with LPS. In endothelial cells, Bß15-42 prevents thrombin-induced stress fiber formation, myosin light chain phosphorylation and RhoA activation. The molecular key for the protective effect of Bß15-42 is the src kinase Fyn, which associates with VE-cadherin-containing junctions. Following exposure to Bß15-42 Fyn dissociates from VE-cadherin and associates with p190RhoGAP, a known antagonists of RhoA activation. The role of Fyn in transducing effects of Bß15-42 is confirmed in Fyn -/- mice, where the peptide is unable to reduce LPS-induced lung edema, whereas in wild type littermates the peptide significantly reduces leak. Our results demonstrate a novel function for Bß15-42. Formerly mainly considered as a degradation product occurring after fibrin inactivation, it has now to be considered as a signaling molecule. It stabilizes endothelial barriers and thus could be an attractive adjuvant in the treatment of shock.
MetadatenAuthor: | Marion Gröger, Waltraud Pasteiner, George Ignatyev, Ulrich Matt, Sylvia Knapp, Alena Atrasheuskaya, Eugenij Bukin, Peter Friedl, Daniela Zinkl, Renate Hofer-Warbinek, Kai ZacharowskiORCiDGND, Peter Petzelbauer, Sonja Reingruber |
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URN: | urn:nbn:de:hebis:30-73121 |
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DOI: | https://doi.org/10.1371/journal.pone.0005391 |
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ISSN: | 1932-6203 |
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Parent Title (English): | PLoS One |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2009/04/29 |
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Date of first Publication: | 2009/04/29 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2009/12/10 |
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Volume: | 4 |
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Issue: | (4): e5391 |
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Note: | Copyright Gröger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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Source: | PLoS ONE. 2009; 4(4): e5391 ; doi: 10.1371/journal.pone.0005391 |
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HeBIS-PPN: | 22055983X |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Licence (German): | Creative Commons - Namensnennung 3.0 |
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