Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice.

Abstract

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-ĸB/NF-ĸB and qRT-PCR for Il-6, Il-1β, Tnf-α, Vegf, and Nf-ĸb 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-ĸB 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.

• Authors: Yohei Tomita, Bertan Cakir, Chi-Hsiu Liu, Zhongjie Fu, Shuo Huang, Steve S Cho, William R Britton, Ye Sun, Mark Puder, Ann Hellström, Saswata Talukdar, Lois E H Smith
• Journal: Angiogenesis (Angiogenesis) Vol. 23 Issue 3 Pg. 385-394 (08 2020) ISSN: 1573-7209 [Electronic] Germany
• PMID: 32140799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• FFAR4 protein, mouse
• NF-kappa B
• Receptors, G-Protein-Coupled

Topics

• Animals
• Choroidal Neovascularization (genetics, metabolism, prevention & control)
• Cytokines (genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• NF-kappa B (genetics, metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)