Document Detail

5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids.
MedLine Citation:
PMID:  21307302     Owner:  NLM     Status:  MEDLINE    
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.
Przemyslaw Sapieha; Andreas Stahl; Jing Chen; Molly R Seaward; Keirnan L Willett; Nathan M Krah; Roberta J Dennison; Kip M Connor; Christopher M Aderman; Elvira Liclican; Arianna Carughi; Dalia Perelman; Yoshihide Kanaoka; John Paul Sangiovanni; Karsten Gronert; Lois E H Smith
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  3     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-10     Completed Date:  2011-05-26     Revised Date:  2013-07-19    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  69ra12     Citation Subset:  IM    
Department of Ophthalmology, Harvard Medical School, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
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MeSH Terms
Angiogenesis Inhibitors / therapeutic use*
Arachidonate 5-Lipoxygenase / genetics,  metabolism*
Blotting, Western
Cell Proliferation / drug effects
Cells, Cultured
Cyclooxygenase 2 / metabolism
Docosahexaenoic Acids / metabolism*
Fatty Acids, Omega-3 / therapeutic use*
Fatty Acids, Omega-6 / therapeutic use
Oxygen / toxicity
PPAR gamma / metabolism
Retinal Diseases / chemically induced,  drug therapy,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
EY016136/EY/NEI NIH HHS; EY017017/EY/NEI NIH HHS; EY017017-04S1/EY/NEI NIH HHS; F32 EY017789/EY/NEI NIH HHS; P01 HD18655/HD/NICHD NIH HHS; R01 EY017017/EY/NEI NIH HHS; R01 EY022275/EY/NEI NIH HHS; //Canadian Institutes of Health Research
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/Fatty Acids, Omega-3; 0/Fatty Acids, Omega-6; 0/PPAR gamma; 25167-62-8/Docosahexaenoic Acids; 7782-44-7/Oxygen; EC 5-Lipoxygenase; EC 2

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