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

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

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)385-394
Number of pages10
JournalAngiogenesis
Volume23
Issue number3
DOIs
Publication statusPublished - 2020 Aug 1
Externally publishedYes

Keywords

  • Age-related macular degeneration (AMD)
  • Free fatty acid receptor 4 (FFAR4)
  • IL-6
  • Laser-induced choroidal neovascularization (CNV)
  • NF-ĸb

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Fingerprint

Dive into the research topics of 'Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice'. Together they form a unique fingerprint.

Cite this