June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Free Fatty Acid Receptor 4 Activation Protects Against Choroidal Neovascularization in Mice
Author Affiliations & Notes
  • Yohei Tomita
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Bertan Cakir
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Chi-Hsiu Liu
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Zhongjie Fu
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Shuo Huang
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Cho Steve
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
  • William Britton
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
  • Yumi Kotoda
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
  • Ye Sun
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Mark Puder
    Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Ann Hellström
    Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden
  • Saswata Talukdar
    Merck & Co., Inc, California, United States
  • Lois E H Smith
    Ophthalmology, Boston Children's Hospital, Massachusetts, United States
    Harvard Medical School, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Yohei Tomita, None; Bertan Cakir, None; Chi-Hsiu Liu, None; Zhongjie Fu, None; Shuo Huang, None; Cho Steve, None; William Britton, None; Yumi Kotoda, None; Ye Sun, None; Mark Puder, None; Ann Hellström, None; Saswata Talukdar, Merck & Co., Inc. (E); Lois Smith, None
  • Footnotes
    Support  Manpei Diabetic Foundation (YT), NIH EY024864, EY017017, EY017017-13S1, BCH IDDRC (1U54HD090255), (LEHS), BCH Manton Center Fellowship and Blind Children’s Center (ZF), Boston Children's Hospital OFD/BTREC/CTREC Faculty Career Development Grant (YS), The German Research Foundation (DFG; to BC [CA1940/1-1]), The Wallenberg Clinical Scholars (AH).
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1938. doi:
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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)

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Abstract

Purpose : 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).

Methods : 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.

Results : 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.

Conclusions : 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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