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Yohei Tomita, Bertan Cakir, Chi-Hsiu Liu, Zhongjie Fu, Shuo Huang, Cho Steve, William Britton, Yumi Kotoda, Ye Sun, Mark Puder, Ann Hellström, Saswata Talukdar, Lois E H Smith; Free Fatty Acid Receptor 4 Activation Protects Against Choroidal Neovascularization in Mice. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1938.
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© ARVO (1962-2015); The Authors (2016-present)
To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD).
Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (FFAR4+/+) and knock out (FFAR4-/-) mice on a C57BL/6J/6N background. The ex vivo choroid sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-κB / NF-κB and qRT-PCR for Il-6, Il-1β, Tnf-α were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from FFAR4+/+ and FFAR4-/- mice were used to assess RPE contribution to inflammation.
The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in FFAR4-/- compared to FFAR4+/+ mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1β) via the NF-κB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of FFAR4-/- mice compared with FFAR4+/+ RPE.
In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV.
This is a 2020 ARVO Annual Meeting abstract.
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