title: Peptide Bbeta(15-42) preserves endothelial barrier function in shock.
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.
authors.affiliation: Department of Dermatology, Medical University Vienna, Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Gröger
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pasteiner
authors.forename: George
authors.initials: G
authors.lastname: Ignatyev
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matt
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.forename: Alena
authors.initials: A
authors.lastname: Atrasheuskaya
authors.forename: Eugenij
authors.initials: E
authors.lastname: Bukin
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
authors.forename: Daniela
authors.initials: D
authors.lastname: Zinkl
authors.forename: Renate
authors.initials: R
authors.lastname: Hofer-Warbinek
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
authors.forename: Sonja
authors.initials: S
authors.lastname: Reingruber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011014:Pneumonia / Q000209:etiology / Q000503:physiopathology; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019595:Severe Dengue / Q000188:drug therapy* / Q000503:physiopathology*; D022502:Stress Fibers / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D005338:Fibrin Fibrinogen Degradation Products; D051417:Focal Adhesion Kinase 1; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D051076:Proto-Oncogene Proteins c-fyn; D013917:Thrombin; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000099152:Cadherin 5; C033786:fibrinogen Bbeta (15-42); C494960:Fyn protein, mouse; C496051:Ptk2 protein, mouse; C526380:RhoA protein, mouse