Journal Article

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

Hofer-Warbinek, Renate, Pasteiner, Waltraud, Atrasheuskaya, Alena, Ignatyev, George, Knapp, Sylvia, Gröger, Marion, Bukin, Eugenij, Matt, Ulrich, Zacharowski, Kai, Reingruber, Sonja, Petzelbauer, Peter, Friedl, Peter, Zinkl, Daniela

2009

Overview

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.

• Publisher: Public Library of Science (PLoS)
• Subject: Amino Acid Sequence / Animals / Antigens, CD - metabolism / Cadherins - metabolism / Capillaries - drug effects / Capillaries - physiopathology / Disease Models, Animal / Endothelium, Vascular - drug effects / Endothelium, Vascular - physiopathology / Fibrin Fibrinogen Degradation Products - chemistry / Fibrin Fibrinogen Degradation Products - pharmacology / Focal Adhesion Kinase 1 - metabolism / Humans / Lipopolysaccharides - toxicity / Male / Mice / Mice, Inbred BALB C / Mice, Knockout / Molecular Sequence Data / Peptide Fragments - chemistry / Peptide Fragments - pharmacology / Pneumonia - etiology / Pneumonia - physiopathology / Proto-Oncogene Proteins c-fyn - deficiency / Proto-Oncogene Proteins c-fyn - genetics / Proto-Oncogene Proteins c-fyn - physiology / Rats / Rats, Sprague-Dawley / rho GTP-Binding Proteins - metabolism / Severe Dengue - drug therapy / Severe Dengue - physiopathology / Stress Fibers - drug effects / Stress Fibers - physiology / Thrombin - pharmacology