Peptide Bbeta(15-42) preserves endothelial barrier function in shock.
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.
Gröger
Marion
M
Department of Dermatology, Medical University Vienna, Vienna, Austria.
Pasteiner
Waltraud
W
Ignatyev
George
G
Matt
Ulrich
U
Knapp
Sylvia
S
Atrasheuskaya
Alena
A
Bukin
Eugenij
E
Friedl
Peter
P
Zinkl
Daniela
D
Hofer-Warbinek
Renate
R
Zacharowski
Kai
K
Petzelbauer
Peter
P
Reingruber
Sonja
S
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
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