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

Item Type:Article
Title:Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization
Creators Name:Hasegawa, E. and Inafuku, S. and Mulki, L. and Okunuki, Y. and Yanai, R. and Smith, K.E. and Kim, C.B. and Klokman, G. and Bielenberg, D.R. and Puli, N. and Falck, J.R. and Husain, D. and Miller, J.W. and Edin, M.L. and Zeldin, D.C. and Lee, K.S.S. and Hammock, B.D. and Schunck, W.H. and Connor, K.M.
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, Oxylipin, Omega-3 Fatty Acids, Lipid Metabolites, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:E7545-E7553
Date:5 September 2017
Official Publication:https://doi.org/10.1073/pnas.1620898114
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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