Next Article in Journal
The New Frontier in Oxytocin Physiology: The Oxytonic Contraction
Next Article in Special Issue
Analysis of Early Cone Dysfunction in an In Vivo Model of Rod-Cone Dystrophy
Previous Article in Journal
Epigenetic Landmarks of Leaf Senescence and Crop Improvement
Previous Article in Special Issue
Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy
Open AccessArticle

Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling

1
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2
Department of Ophthalmology and the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3
AsclepiX Therapeutics, Inc., Baltimore, MD 21211, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 5142; https://doi.org/10.3390/ijms21145142
Received: 15 June 2020 / Revised: 10 July 2020 / Accepted: 16 July 2020 / Published: 21 July 2020
Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization. View Full-Text
Keywords: AXT107; peptide therapeutic; ocular diseases; endothelial activation; vascular permeability; vascular leakage; TNFα; NF-κB; IκBα; leukostasis; VCAM-1 AXT107; peptide therapeutic; ocular diseases; endothelial activation; vascular permeability; vascular leakage; TNFα; NF-κB; IκBα; leukostasis; VCAM-1
Show Figures

Graphical abstract

MDPI and ACS Style

Mirando, A.C.; Lima e Silva, R.; Chu, Z.; Campochiaro, P.A.; Pandey, N.B.; Popel, A.S. Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling. Int. J. Mol. Sci. 2020, 21, 5142. https://doi.org/10.3390/ijms21145142

AMA Style

Mirando AC, Lima e Silva R, Chu Z, Campochiaro PA, Pandey NB, Popel AS. Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling. International Journal of Molecular Sciences. 2020; 21(14):5142. https://doi.org/10.3390/ijms21145142

Chicago/Turabian Style

Mirando, Adam C.; Lima e Silva, Raquel; Chu, Zenny; Campochiaro, Peter A.; Pandey, Niranjan B.; Popel, Aleksander S. 2020. "Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling" Int. J. Mol. Sci. 21, no. 14: 5142. https://doi.org/10.3390/ijms21145142

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop