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

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.

• Authors: Eiichi Hasegawa, Saori Inafuku, Lama Mulki, Yoko Okunuki, Ryoji Yanai, Kaylee E Smith, Clifford B Kim, Garrett Klokman, Diane R Bielenberg, Narender Puli, John R Falck, Deeba Husain, Joan W Miller, Matthew L Edin, Darryl C Zeldin, Kin Sing Stephen Lee, Bruce D Hammock, Wolf-Hagen Schunck, Kip M Connor
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 36 Pg. E7545-E7553 (09 05 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28827330 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids, Unsaturated
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2C8
• Epoxide Hydrolases

Topics

• Animals
• Choroidal Neovascularization (metabolism)
• Cytochrome P-450 CYP2C8 (metabolism)
• Cytochrome P-450 Enzyme System (metabolism)
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Epoxide Hydrolases (metabolism)
• Fatty Acids, Unsaturated (metabolism)
• Leukocytes (metabolism)
• Lipid Metabolism (physiology)
• Macular Degeneration (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Second Messenger Systems (physiology)