June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Targeting NF-κB signaling reduces retinal neovascularization by inhibiting MMP-2/9 expression and promoting cell apoptosis and macrophage polarization shift via integrinα5β1
Author Affiliations & Notes
  • AILING SUI
    ophthalmology, ruijin hospital,shanghai jiao tong university school of medicine, Shanghai, China
  • BING XIE
    ophthalmology, ruijin hospital,shanghai jiao tong university school of medicine, Shanghai, China
  • Footnotes
    Commercial Relationships   AILING SUI, None; BING XIE, None
  • Footnotes
    Support   National Nature Science Foundation of China 81470639 and 81570853
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5381. doi:
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      AILING SUI, BING XIE; Targeting NF-κB signaling reduces retinal neovascularization by inhibiting MMP-2/9 expression and promoting cell apoptosis and macrophage polarization shift via integrinα5β1. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5381.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Anti-VEGF treatment can reduce retinal neovascularization (NV) and tumor NV, but this treatment is effective in only some patients with ocular NV and has some side effect. Nuclear Factor-κB signaling participates in regulating tumor angiogenesis and metastasis. However, its mechanism of action in retinal neovascularization remains unclear. We hypothesize that targeting NF-κB signaling reduces retinal neovascularization by inhibiting matrix metalloproteinase-2/9 (MMP-2/9) expression, promoting cell apoptosis and macrophage polarization shift via integrin α5β1.

Methods : 7-day-old mice with a C57BL/6 genetic background were exposed to 75% ± 3% oxygen for 5 days to establish the mice model of oxygen-induced retinopathy (OIR). At postnatal day 12(P12), both eyes injected intravitreously with 1 μL of different concentrate pyrrolidinedithiocarbamate (PDTC), ATN-161, or PBS. The retinas were used to carry out immunofluorescence and retinal flat-mount, examine expression of NF-κB signaling, integrin α5β1, MMP-2/9 and macrophage polarization-associated genes by RT-PCR and western blot. TUNEL were used to explore cell apoptosis of retinal neovascularization

Results : In OIR mice, the protein expression of phosphorylated IκBα (p-IκBα) and p-p65 increased significantly compared with that in age-matched controls (n=3, P<0.01). The mice given PDTC, an inhibitor of NF-κB signaling activation, had significantly reduced retinal NV(RNV) (n=14, p<0.05), expression of integrin α5β1 (n=6, p<0.001), MMP-2(n=6, p<0.001) and MMP-9(n=7, p=0.048). Blocking integrin α5β1 by ATN-161 strongly inhibited expression of MMP-2(n=6, p=0.04), MMP-9(n=7, p=0.001) and RNV(n=10,p<0.01). PDTC and ATN-161 promoted cell apoptosis of NV in mice with OIR. The expression of M1 macrophage associated cytokines decreased and M2 macrophage associated cytokines increased in OIR mice treated with either PDTC or ATN-161.

Conclusions : Our results were consistent with our hypothesis: In ocular NV, NF-κB signaling activation via integrin α5β1 promoted expression of MMP-2/9. Blocking activation of NF-κB signaling and expression of integrin α5β1 promoted cell apoptosis of ocular NV and polarization of M1 macrophage to M2 macrophage. These findings could potentially results in the development of a novel therapy to treat NV eye diseases as an adjuvant to anti-VEGF therapy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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