ω-3 and ω-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases

Abstract

Neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, threaten the visual health of children and adults. Current treatment options, including anti-vascular endothelial growth factor therapy and laser retinal photocoagulation, have limitations and are associated with adverse effects; therefore, the identification of additional therapies is highly desirable. Both clinical and experimental studies show that dietary ω-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) reduce retinal and choroidal angiogenesis. The ω-3 LC-PUFA metabolites from 2 groups of enzymes, cyclooxygenases and lipoxygenases, inhibit [and the ω-6 (n-6) LC-PUFA metabolites promote] inflammation and angiogenesis. However, both of the ω-3 and the ω-6 lipid products of cytochrome P450 oxidase 2C promote neovascularization in both the retina and choroid, which suggests that inhibition of this pathway might be beneficial. This review summarizes our current understanding of the roles of ω-3 and ω-6 LC-PUFAs and their enzymatic metabolites in neovascular eye diseases.

Keywords: age-related macular degeneration; diabetic retinopathy; lipid metabolism; long-chain polyunsaturated fatty acid; retinopathy of prematurity.

FIGURE 1

Chemical structures of AA, DHA, and EPA. In ω-6 LC-PUFAs (AA), the first double bond is located after the sixth-carbon atom from the ω end, whereas the third-carbon atom is followed by the first double bond in ω-3 LC-PUFAs (DHA and EPA). AA, arachidonic acid; LC-PUFA, long-chain PUFAs.

FIGURE 2

Progression of retinopathy of prematurity. Oxygen tension is low, and vascular growth is normal in utero. After premature birth, retinal vessel growth stops due to hyperoxia and loss of the nutrients, including ω-3 LCPUFAs. As the retina matures and metabolic demand increases, hypoxia results. The hypoxic retina stimulates expression of proangiogenic factors, which stimulate retinal neovascularization. LCPUFA, long-chain PUFAs. Reproduced from reference with permission.

FIGURE 3

ω-3 LC-PUFAs preserve retinal function in db/db mice. (A) Type 2 diabetic db/db mice fed defined rodent feed pellets with 10% (wt:wt) safflower oil containing either 2% ω-3 LC-PUFAs (1% DHA and 1% EPA) or 2% ω-6 LC-PUFAs (AA). (B) Representative electroretinographic wave from mice fed ω-3 or ω-6 LC-PUFAs. (C) Saturating amplitude of responses originating in photoreceptors and bipolar cells from db/db mice fed a ω-3 and ω-6 LC-PUFA–enriched diet. Light stimulation triggered the hyperpolarizaton of the photoreceptors (“a” wave), resulting in a decreased release of neurotransmitter, which subsequently led to the depolarization of bipolar cells (“b” wave). The amplitude of the “a” wave was from the baseline to the negative trough of the “a” wave; the amplitude of the “b” wave was from the trough of a wave to the peak of the “b” wave. The data were normalized by the values in age-matched heterozygotes fed normal feed pellets (gray shading). A significant attenuation was observed in the ω-6 LC-PUFA group. AA, arachidonic acid; LC-PUFA, long-chain PUFAs. Reproduced from reference with permission.

FIGURE 4

Schematic of the COX and LOX pathways metabolizing ω-6 and ω-3 LC-PUFAs. Liberated ω-6 and ω-3 LC-PUFAs are rapidly metabolized by COX and LOX enzymes and generated the pathway-specific lipid metabolites PGs, TXs, LTs, HETEs, resolvins, HDHAs, and neuroprotectins. The metabolites derived from ω-6 LC-PUFAs are proinflammatory and proangiogenic, whereas those derived from ω-3 LC-PUFAs are anti-inflammatory and antiangiogenic. COX, cyclooxygenase; HDHA, hydroxydocosahexaenoic acid; HETE, hydroxyeicosatetraenoic acid; LC-PUFA, long-chain PUFA; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane.

FIGURE 5

The CYP pathway is a potential pharmaceutical target to treat neovascular eye diseases. The CYP2C metabolites derived from both ω-6 and ω-3 LCPUFAs promote pathological ocular angiogenesis. CYP2C inhibition adds to ω-3 LCPUFA protection against retinal and choroidal neovascularization. AA, arachidonic acid; CYP, cytochrome P450 oxidase; EDP, epoxydocosapentaenoic acid; EET, epoxyeicosatrienoic acid; GCL, ganglion cell layer; INL, inner nuclear layer; LCPUFA, long-chain PUFAs; ONL, outer nuclear layer; RPE, retinal pigment epithelium. Reproduced from references and with permission.