Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/ijms21145142
Keywords
AXT107; peptide therapeutic; ocular diseases; endothelial activation; vascular permeability; vascular leakage; TNF alpha; NF-kappa B; I kappa B alpha; leukostasis; VCAM-1
Funding
- NIH [F32CA210482, R01EY028996, R01HL101200, R44EY027632]
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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 alpha v beta 3 and alpha 5 beta 1 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 alpha (TNF alpha), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNF alpha-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNF alpha and Ang2 while also preventing inhibitor of nuclear factor-kappa B alpha (I kappa B alpha) degradation directly through Tie2 signaling. This recovery of I kappa B alpha prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) nuclear localization, thereby blocking NF-kappa B-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.
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