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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Published in:American journal of physiology. Lung cellular and molecular physiology Vol. 300; no. 6; p. L851
Main Authors: David, Sascha, Ghosh, Chandra C, Kümpers, Philipp, Shushakova, Nelli, Van Slyke, Paul, Khankin, Eliyahu V, Karumanchi, S Ananth, Dumont, Dan, Parikh, Samir M
Format: Journal Article
Language:English
Published: United States 01.06.2011
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1522-1504
1522-1504
DOI:10.1152/ajplung.00459.2010