Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality

A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We...

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Vydané v:	American journal of physiology. Lung cellular and molecular physiology Ročník 300; číslo 6; s. L851
Hlavní autori:	David, Sascha, Ghosh, Chandra C, Kümpers, Philipp, Shushakova, Nelli, Van Slyke, Paul, Khankin, Eliyahu V, Karumanchi, S Ananth, Dumont, Dan, Parikh, Samir M
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.06.2011
Predmet:	Animals Blotting, Western Capillary Permeability - drug effects Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Endotoxemia - chemically induced Endotoxemia - mortality Endotoxemia - prevention & control Endotoxins - adverse effects Humans Immunoenzyme Techniques Lipopolysaccharides - pharmacology Lung Injury - chemically induced Lung Injury - mortality Lung Injury - prevention & control Male Mice Mice, Inbred C57BL Peptide Fragments - chemical synthesis Peptide Fragments - pharmacology Polyethylene Glycols - administration & dosage Polyethylene Glycols - chemistry Polyethylene Glycols - metabolism Receptor, TIE-2 - agonists Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Survival Rate
ISSN:	1522-1504, 1522-1504
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Shrnutí:	A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ∼70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% (n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% (n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1522-1504 1522-1504
DOI:	10.1152/ajplung.00459.2010