| DOI | Trouver le DOI : https://doi.org/10.1002/bit.27580 |
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| Auteur | Rechercher : Liu, PanIdentifiant ORCID : https://orcid.org/0000-0002-3066-652X; Rechercher : Ryczko, Michael; Rechercher : Xie, Xinfang; Rechercher : Baardsnes, Jason1; Rechercher : Lord‐Dufour, Simon1; Rechercher : Duroche, Yves1; Rechercher : Hicks, Emily Anne; Rechercher : Taiyab, Aftab; Rechercher : Sheardown, Heather; Rechercher : Quaggin, Susan E.; Rechercher : Jin, Jing |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Bailleur de fonds | Rechercher : National Institutes of Health |
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| Format | Texte, Article |
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| Sujet | angiopoetin 1; angiopoietin‐Tie2 pathway; chimeric protein; vascular perme |
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| Résumé | 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. |
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| Date de publication | 2020-09-24 |
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| Maison d’édition | Wiley |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | 29c15f39-f7a3-45c6-a33b-80d74a107e37 |
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| Enregistrement créé | 2023-02-20 |
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| Enregistrement modifié | 2023-02-20 |
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