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Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7545-E7553. doi: 10.1073/pnas.1620898114. Epub 2017 Aug 21.

Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization.

Author information

1
Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114.
2
Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115.
3
Department of Biochemistry, University of Texas Southwestern, Dallas, TX 75390.
4
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
5
Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616.
6
Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; bdhammock@ucdavis.edu kip_connor@meei.harvard.edu.
7
Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany.
8
Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114; bdhammock@ucdavis.edu kip_connor@meei.harvard.edu.

Abstract

Age-related macular degeneration (AMD) is the most common cause of blindness for individuals age 50 and above 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 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. Using transgenic mice with altered CYP lipid biosynthetic pathways in a mouse model of laser-induced CNV, we characterized the role of these lipid metabolites in regulating neovascular disease. We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of the monooxygenase CYP2C8 or genetic ablation or 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. These results suggest that CYP lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases.

KEYWORDS:

P450; choroidal neovascularization; lipid metabolites; omega-3 fatty acids; oxylipin

PMID:
28827330
PMCID:
PMC5594641
DOI:
10.1073/pnas.1620898114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: Massachusetts Eye and Ear Infirmary holds a patent application on anticomplement therapeutics in ocular cell death titled Cyp450 lipid metabolites reduce inflammation and angiogenesis (MEEI WO 2014110261 A1: PCT/US2014/010880) (of which K.M.C. and R.Y. are inventors) and has a pending application of the use of sEH inhibitors in inflammation and angiogenesis (of which K.M.C., E.H., and B.D.H. are inventors). Additionally, Massachusetts Eye and Ear has a proprietary interest in photodynamic therapy for conditions involving unwanted ocular neovascularization and has received financial remuneration related to this technology. J.W.M. receives a share of the same in accordance with institutional guidelines. Max Delbruck Center for Molecular Medicine and University of Texas Southwestern hold a patent family on novel eicosanoid derivatives, also encompassing C21 and its use (WO 2010/081683, PCT/EP2010/000140) (of which W.-H.S., J.R.F., and N.P. are inventors). Max Delbruck Center for Molecular Medicine holds a pending patent application of the use of novel eicosanoid derivatives in indications, associated with inflammation and neovascularization (of which W.-H.S. is inventor).

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