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PLoS One. 2009;4(4):e5391. doi: 10.1371/journal.pone.0005391. Epub 2009 Apr 29.

Peptide Bbeta(15-42) preserves endothelial barrier function in shock.

Author information

1
Department of Dermatology, Medical University Vienna, Vienna, Austria.

Erratum in

  • PLoS One. 2009;4(6) doi: 10.1371/annotation/9ae032a2-c48d-46d9-9f8f-d3f401714e42.

Abstract

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 Bbeta15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. The ability of Bbeta15-42 to preserve endothelial barriers is confirmed in rats i.v.-injected with LPS. In endothelial cells, Bbeta15-42 prevents thrombin-induced stress fiber formation, myosin light chain phosphorylation and RhoA activation. The molecular key for the protective effect of Bbeta15-42 is the src kinase Fyn, which associates with VE-cadherin-containing junctions. Following exposure to Bbeta15-42 Fyn dissociates from VE-cadherin and associates with p190RhoGAP, a known antagonists of RhoA activation. The role of Fyn in transducing effects of Bbeta15-42 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 Bbeta15-42. 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.

PMID:
19401765
PMCID:
PMC2670535
DOI:
10.1371/journal.pone.0005391
[Indexed for MEDLINE]
Free PMC Article

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