Inhibition of integrin α5β1 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model

Autor: Bing Xie, Yujuan Cai, Qing Lu, Yushuo Gao, Ailing Sui, Yisheng Zhong, Anna M. Demetriades, Xi Shen, Yanji Zhu
Rok vydání: 2018
Předmět:
Vascular Endothelial Growth Factor A
0301 basic medicine
Opsin
Angiogenesis Inhibitors
Retinal Neovascularization
Neovascularization
Mice
chemistry.chemical_compound
0302 clinical medicine
Basic Science
Fluorescent Antibody Technique
Indirect
medicine.diagnostic_test
Retinal detachment
Inflammasome
Sensory Systems
Anti-Bacterial Agents
Specific Pathogen-Free Organisms
Vascular endothelial growth factor
Doxycycline
Integrin α5β1
medicine.symptom
Oligopeptides
Integrin alpha5beta1
Signal Transduction
medicine.drug
Genetically modified mouse
Tet/opsin/VEGF transgenic mice
Blotting
Western
Mice
Transgenic
Real-Time Polymerase Chain Reaction
ATN-161
Capillary Permeability
03 medical and health sciences
Cellular and Molecular Neuroscience
Western blot
NLR Family
Pyrin Domain-Containing 3 Protein
medicine
Animals
Humans
RNA
Messenger
Retinal Detachment
Retinal
medicine.disease
Molecular biology
NLRP3 inflammasome
Disease Models
Animal
Ophthalmology
030104 developmental biology
chemistry
030221 ophthalmology & optometry
Endothelium
Vascular
Zdroj: Graefe's Archive for Clinical and Experimental Ophthalmology
ISSN: 1435-702X
0721-832X
DOI: 10.1007/s00417-018-3940-x
Popis: Purpose To assess the effect of inhibiting integrin α5β1 by ATN-161 on vascular endothelial growth factor (VEGF)-induced neovascularization (NV) and leakage causing retinal detachment in adult Tet/opsin/VEGF transgenic mice, and characterize the underlying mechanism of its function. Method Retinas from adult Tet/opsin/VEGF transgenic mice and human retinal endothelial cells (HRECs) exposed to VEGF (treated with ATN-161 or PBS) were used to carry out immunofluorescence, RT-PCR and western blot to examine expression levels of integrin α5β1 and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome. Retinal frozen section analysis was used to assess NV and leakage causing retinal detachment. Results In comparison to normal-treated mice, doxycycline-treated Tet/opsin/VEGF transgenic mice showed severe retinal detachment and higher integrin α5β1 expression. Furthermore, the retinal detachment was inhibited significantly by ATN-161. Additionally, ATN-161 treatment was associated with a conspicuous reduction in NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and mature interleukin-1β expression levels in the retinas of Tet/opsin/VEGF transgenic mice treated with doxycycline as well as in HRECs exposed to VEGF. Conclusion ATN-161, an antagonist of integrin α5β1, is a promising treatment for retinal neovascularization (RNV), and its retinal protection role appears to take effect through inhibition of NLRP3 inflammasome activity.
Databáze: OpenAIRE
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