Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 36, Pages E7545-E7553Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1620898114
Keywords
P450; choroidal neovascularization; oxylipin; omega-3 fatty acids; lipid metabolites
Categories
Funding
- Research to Prevent Blindness
- Department of Ophthalmology, Harvard University
- Massachusetts Eye and Ear Infirmary
- Massachusetts Lions Eye Research Fund
- BrightFocus Foundation
- West Coast Metabolomics Center [NIH 1U24DK097154]
- Japan Society for the Promotion of Science Postdoctoral Fellowships
- NIH, National Institute of Environmental Health Sciences (NIEHS) [Z01 E5025034]
- Robert A. Welch Foundation [1-0011]
- NIH [HL111392, K99ES024806, R00ES024806]
- NIEHS [R01ES002710]
- NIEHS/Superfund Research Program [P42 E5004699]
- Special Scholar Award
- Medical Student Fellowship
- [R01EY022084/S1]
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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.
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