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 microglialderived 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.

Exploring Valuable Lipids in Diatoms

“…a (Kabara et al, 1972;Hallahan and Garland, 2005;Desbois et al, 2008;Lafourcade et al, 2011;Sapieha et al, 2011;Valenzuela et al, 2012;Hamilton et al, 2015;Jiang et al, 2016). b (d'ippolito et al, 2015).…”

“…Omega-3 fatty acids such as EPA and DHA have been found to have effects in alleviating a number of health conditions (e.g., arteriosclerosis, hypertension, inflammation, microbial, viral, and tumor activity). EPA and DHA play important roles in protecting cardiovascular system (Sapieha et al, 2011), vision (Hallahan and Garland, 2005), and treating psychiatric disorders (Lafourcade et al, 2011).…”

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

“…A widely accepted theory to explain the health-promoting effects of omega-3 fatty acids is that they suppress the metabolism of omega-6 arachidonic acid (ARA) to form proangiogenic or proinflammatory eicosanoids or serve as alternative substrates to generate omega-3 lipid mediators with beneficial actions (9). Indeed, the metabolism of omega-3 fatty acids by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes generates 3-series prostaglandins (10,11) and leukotrienes (12), as well as unique omega-3 autacoids such as resolvins and protectins (13), which have antiinflammatory or antiangiogenic effects.…”

Encapsulated specialty oils commercialized in São Paulo state, Brazil: evaluation of identity (fatty acid profile) and compliance of fatty acids and Vitamin E contents with nutrition labeling

“…Studies have suggested numerous benefits of omega-3 fatty acids such as prevention of cardiovascular diseases, inflammation, allergies, hypertension, arthritis, some cancers, and multiple sclerosis among others (LIMA et al, 2007;RUIZ-RODRIGUEZ;REGLERO;IBAÑEZ, 2010;SAPIEHA et al, 2011).…”