期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 3, 期 69, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3001571
关键词
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资金
- NIH [EY017017, EY017017-04S1, EY016136]
- Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center [P01 HD18655]
- Research to Prevent Blindness
- Alcon Research Institute
- MacTel Foundation
- Roche Foundation for Anemia Research
- V. Kann Rasmussen Foundation
- Canadian Institutes of Health Research
- Charles A. King Trust
- Canadian National Institute for the Blind
- Deutsche Forschungsgemeinschaft
- Juvenile Diabetes Research Foundation International
- William Randolph Hearst Award [F32 EY017789]
Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. We have previously demonstrated that diets enriched in omega-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglialderived tumor necrosis factor-alpha. To better understand the protective effects of omega-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. omega-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary omega-3 PUFAs. This protective effect was due to 5-LOX oxidation of the omega-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4-HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPAR gamma), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that omega-3 PUFAs may be profitably used as an alternative or supplement to current anti-vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of omega-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary omega-3 PUFA.
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