Researchers from Massachusetts Eye and Ear/Schepens Eye Research Institute, Harvard Medical School and other institutions have demonstrated for the first time that the omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs), DHA and EPA, and their specific bioactive products derived from the cytochrome P450 (CYP) pathway, can influence choroidal neovascularization (CNV) and vascular leakage by modulating micro-environmental immune cell recruitment to the site of these lesions. Their findings will be published in PNAS Online Early Edition the week of June 16-20, 2014.
“These are the first results showing that omega (ω)-3 LCPUFAs and their CYP derived metabolites can regulate choroidal angiogenesis in vivo. The fact that this can be accomplished with physiologically relevant naturally occurring lipid metabolites is of significant clinical interest as these molecules are readily available and considered to be safe. Our findings not only show promising therapeutic potential for resolution of neovascular AMD, but also for other conditions or diseases that involve pathologic angiogenesis and inflammation,” said Kip Connor, Ph.D., Assistant Professor in Ophthalmology at Harvard Medical School and senior author of the paper.
The omega (ω)-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. To evaluate the effect of LCPUFAs on CNV development, researchers fed mice one of three experimental diets beginning two weeks before CNV induction by laser photocoagulation. The experimental diets were enriched with either ω-3 or ω-6 LCPUFAs, or in the case of the control diet, devoid of the primary ω-3 or ω-6 LCPUFAs. The lesion size and vascular leakage were significantly smaller in animals fed with ω-3 LCPUFAs. To gain mechanistic insight into the effect of dietary ω-3 LCPUFAs on CNV regression, researchers analyzed the lipid profiles of these mice and identified endogenous CYP-generated metabolites. Specifically, 17,18-EEQ and 19,20-EDP, derived from the CYP-pathway were identified by liquid chromatography- mass spectrometry (LC–MS/MS) and found to confer protection. Systemic immune-cell recruitment and adhesion-molecule regulation were significantly dampened in mice receiving ω-3s, thereby suppressing inflammation that is thought to exacerbate this disease. These findings provide a unique mechanism whereby specific CYP derived lipid metabolites regulate angiogenesis in a mouse model of AMD,” said lead author Ryoji Yanai, M.D., Ph.D.
The researchers demonstrated that dietary supplementation of omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) mediates choroidal neovessel regression in a well-characterized murine model of neovascular AMD. The cytochrome P450 (CYP) enzymes catalyze the epoxidation of these ω-3 LCPUFAs to form the eicosanoids 17,18-epoxyeicosatetraenoic acid (EEQ) and 19,20-epoxydocosapentaenoic acid (EDP), which were identified as key lipid mediators of disease resolution. Their findings show promising therapeutic potential in AMD disease resolution.
“Given the prevalence of neovascular eye disease, the potential impact of this study is highly significant. We have identified unique endogenous lipid biometabolites that are able to inhibit pathologic retinal angiogenesis, a major driver of vision loss worldwide. It is our hope that future studies will allow us to develop specific therapeutics that harness this knowledge resulting in a greater visual outcome and quality of life for patients suffering from these sight threatening diseases,” Dr. Connor said.
Research reported in this publication was supported by a Special Scholar Award and unrestricted grant from Research to Prevent Blindness; the Massachusetts Lions Eye Research Fund, and an award from the Japan Eye Bank Association (to R.Y.). Additionally, Research reported in this publication was supported by National Eye Institute of the National Institutes of Health under award numbers: R01EY022084/S1, T32EY007145 and P30EY014104. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
A full list of researchers can be found in the paper.
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Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. Led by the Eaton-Peabody Laboratory in Otology, the Howe Laboratory in Ophthalmology, the Berman-Gund Laboratory and Schepens Eye Research Institute, Mass. Eye and Ear in Boston is the world's largest vision and hearing research center, offering hope and healing to patients everywhere through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report’s “Best Hospitals Survey” has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as among the top hospitals in the nation.
Proceedings of the National Academy of Sciences