June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Cytochrome P450 monooxygenase lipid metabolites regulate choroidal neovascularization in the eye: contribution of the soluble epoxide hydrolase.
Author Affiliations & Notes
  • Kip M Connor
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Saori Inafuku
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Clifford Kim
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Deeba Husain
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Joan W Miller
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Eiichi Hasegawa
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Kip Connor, MEEI (P), Novartis - Spouse (E), OMEICOS (F), OMEICOS (C); Saori Inafuku, None; Clifford Kim, None; Deeba Husain, None; Joan Miller, ALCON (C), Amgen, Inc (C), KalVista Pharmaceuticals Ltd. (C), Maculogix, Inc. (C), ONL Therapeutics, LLC (P), Valeant Pharmaceuticals (P); Eiichi Hasegawa, None
  • Footnotes
    Support  This study was supported by a Special Scholar Award (to K.M.C.), Medical Student Fellowship Grant (to C.B.K.), and an unrestricted grant (to J.W.M.) from Research to Prevent Blindness; the Massachusetts Lions Eye Research Fund); by Grants R01EY022084/S1 (to K.M.C.), and by the BrightFocus Foundation (K.M.C.).
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1933. doi:
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      Kip M Connor, Saori Inafuku, Clifford Kim, Deeba Husain, Joan W Miller, Eiichi Hasegawa; Cytochrome P450 monooxygenase lipid metabolites regulate choroidal neovascularization in the eye: contribution of the soluble epoxide hydrolase.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1933.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) is the most common cause of blindness for the elderly in the developed world. Abnormal growth of choroidal blood vessels, or choroidal neovascularization (CNV), is a hallmark of the neovascular (wet) form of advanced AMD and leads to significant vision loss. A growing body of evidence supports a strong link between neovascular disease and inflammation. Metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) derived from the cytochrome P450 (CYP) monooxygenase pathway serve as vital second messengers that regulate a number of hormones and growth factors involved in inflammation and vascular function.

Methods : The present study adheres to ARVO’s Statement for the Use of Animals in Ophthalmic and Vision Research. Utilizing a mouse model of CNV, we characterized the role of these lipid metabolites in regulating neovascular disease.

Results : We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of epoxygenase CYP2C8 or genetic ablation/inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development. In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost. We found that these molecules work in part through their ability to regulate the expression of key leukocyte adhesion molecules, on both leukocytes and endothelial cells, thereby mediating leukocyte recruitment.

Conclusions : These results suggest that CYP-derived lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases. Inhibition of sEH prolonged the bioavailability of these potent bioactive lipids and conferred increased protection in the laser-induced CNV model.

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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