title: 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids.
abstract: 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 ω-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 microglial-derived tumor necrosis factor-α. To better understand the protective effects of ω-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. ω-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 ω-3 PUFAs. This protective effect was due to 5-LOX oxidation of the ω-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 γ (PPARγ), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that ω-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 ω-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 ω-3 PUFA.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Molly R
authors.initials: MR
authors.lastname: Seaward
authors.forename: Keirnan L
authors.initials: KL
authors.lastname: Willett
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Krah
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Dennison
authors.forename: Kip M
authors.initials: KM
authors.lastname: Connor
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Aderman
authors.forename: Elvira
authors.initials: E
authors.lastname: Liclican
authors.forename: Arianna
authors.initials: A
authors.lastname: Carughi
authors.forename: Dalia
authors.initials: D
authors.lastname: Perelman
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
authors.forename: John Paul
authors.initials: JP
authors.lastname: Sangiovanni
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D043371:Fatty Acids, Omega-6 / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D010100:Oxygen / Q000633:toxicity; D047495:PPAR gamma / Q000378:metabolism; D012164:Retinal Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020533:Angiogenesis Inhibitors; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D047495:PPAR gamma; D004281:Docosahexaenoic Acids; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D010100:Oxygen