PUBLICATION
Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis
- Authors
- Lennikov, A., Mirabelli, P., Mukwaya, A., Schaupper, M., Thangavelu, M., Lachota, M., Ali, Z., Jensen, L., Lagali, N.
- ID
- ZDB-PUB-180115-4
- Date
- 2018
- Source
- Angiogenesis 21(2): 267-285 (Journal)
- Registered Authors
- Keywords
- Cornea, IKK2, IMD0354, NF-κB, Neovascularization, VEGF
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Benzamides/pharmacology*
- Cornea/metabolism*
- Cornea/pathology
- Corneal Neovascularization/drug therapy*
- Corneal Neovascularization/genetics
- Corneal Neovascularization/metabolism
- Corneal Neovascularization/pathology
- Eye Proteins/antagonists & inhibitors*
- Eye Proteins/genetics
- Eye Proteins/metabolism
- Human Umbilical Vein Endothelial Cells
- Humans
- I-kappa B Kinase/antagonists & inhibitors*
- I-kappa B Kinase/genetics
- I-kappa B Kinase/metabolism
- Keratitis/drug therapy*
- Keratitis/genetics
- Keratitis/metabolism
- Keratitis/pathology
- Male
- NF-kappa B/genetics
- NF-kappa B/metabolism*
- Rats
- Rats, Wistar
- Signal Transduction/drug effects*
- Signal Transduction/genetics
- Zebrafish
- PubMed
- 29332242 Full text @ Angiogenesis
Citation
Lennikov, A., Mirabelli, P., Mukwaya, A., Schaupper, M., Thangavelu, M., Lachota, M., Ali, Z., Jensen, L., Lagali, N. (2018) Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis. Angiogenesis. 21(2):267-285.
Abstract
Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-κB signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-κB activation through selective blockade of the IKK complex IκB kinase β (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNFα-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-α expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-κB by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-κB signaling in the development of pathologic corneal neovascularization.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping