New soluble angiopoietin analog of Hepta‐ANG1 prevents pathological vascular leakage

Vascular leak is a key driver of organ injury in diseases, and strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the angiopoietin-1 (ANG1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. He...

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Vydáno v:	Biotechnology and bioengineering Ročník 118; číslo 1; s. 423 - 432
Hlavní autoři:	Liu, Pan, Ryczko, Michael, Xie, Xinfang, Baardsnes, Jason, Lord‐Dufour, Simon, Duroche, Yves, Hicks, Emily Anne, Taiyab, Aftab, Sheardown, Heather, Quaggin, Susan E, Jin, Jing
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Wiley 01.01.2021 Wiley Subscription Services, Inc
Témata:	angiopoetin 1 Angiopoietin Angiopoietin-1 - biosynthesis Angiopoietin-1 - genetics Angiopoietin-1 - pharmacology angiopoietin‐Tie2 pathway Animals chimeric protein Complement C4b-Binding Protein - biosynthesis Complement C4b-Binding Protein - genetics Complement C4b-Binding Protein - pharmacology Complement component C4 Extracellular matrix Female Fusion protein Growth factors HEK293 Cells Human Umbilical Vein Endothelial Cells - metabolism Humans Inflammation Injection Injury prevention Intravenous administration Kinases Leakage Lipopolysaccharides Mice Mice, Inbred BALB C Oligomerization Permeability Phosphorylation Protein Domains Protein-tyrosine kinase Proteins Rabbits Recombinant Fusion Proteins - biosynthesis Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - pharmacology Respiratory distress syndrome Respiratory Distress Syndrome - drug therapy Respiratory Distress Syndrome - metabolism Respiratory Distress Syndrome - pathology Sepsis Sepsis - drug therapy Sepsis - metabolism Sepsis - pathology Signal transduction Stability Tyrosine Vascular Diseases - drug therapy Vascular Diseases - metabolism Vascular Diseases - pathology Vascular endothelial growth factor vascular perme vascular permeability angiopoetin 1 vascular permeability angiopoietin-Tie2 pathway chimeric protein
ISSN:	1097-0290, 0006-3592, 1097-0290
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Shrnutí:	Vascular leak is a key driver of organ injury in diseases, and strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the angiopoietin-1 (ANG1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANG1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANG1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α. We refer to this new fusion protein biologic as Hepta-ANG1, which forms a stable heptamer and induces Tie2 phosphorylation in cultured cells, and in the lung following intravenous injection of mice. Injection of Hepta-ANG1 ameliorates vascular endothelial growth factor- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability. The new Hepta-ANG1 fusion is easy to produce and displays remarkable stability with high multimericity that can potently activate Tie2. It could be a new candidate ANG1 mimetic therapy for treatments of inflammatory vascular leak, such as acute respiratory distress syndrome and sepsis. NRC publication: Yes
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1097-0290 0006-3592 1097-0290
DOI:	10.1002/bit.27580