Revealing How Omega-3s Work against Retinopathy

Deciphering Pathways Could Pay Dividends

The omega-3 fatty acids EPA and DHA appear to play an important role in thwarting the new growth of irregular blood vessels in the retina. For example, the omega-3s have been shown to protect against retinal angiogenesis in an animal model of retinopathy and higher omega-3 intake has also been found to correlate with decreased neovascularization in AREDS participants. However, we still don’t know exactly which lipid pathways and which molecules govern specific protective effects.

Deciphering the pathways by which omega-3s block abnormal vessel growth in the eye could lead to the development of new targeted treatments to augment the currently used anti-VEGF approaches to treating retinopathy. It could also tell us whether common inhibitors of omega-3 related enzymes such as aspirin and NSAIDs can be used without losing the beneficial effect of these dietary fatty acids.

Background: Meet the COX and LOX Families

The principal enzymatic pathways that convert the omega-3 and omega-6 fatty acids into bioactive metabolites are the cyclooxygenases (COXs) and the lipoxygenases (LOXs).

The COXs play a primary role in producing prostaglandins (which mediate inflammatory and anaphylactic reactions), thromboxanes (mediators of vessel constriction), and prostacyclins (which are involved in the resolution phase of inflammation).

The LOXs, on the other hand, generate biologically active products such as the leukotrienes, lipoxins, and the recently identified omega 3–derived resolvins and protectins. Resolvins and (neuro)protectins, which can be formed from both EPA and DHA, have very potent anti-inflammatory and immune-regulating actions.

Bottom line is that the beneficial effects of the omega-3s are mostly mediated by these hormone-like compounds derived via the COX and LOX enzymes.

Study Details

Montreal, UC Berkeley, the NEI and elsewhere, sought to clarify the overall contribution of COX and LOX enzymes in blocking destructive neovascularization.

In brief, omega-3 diets were fed to 4 lines of mice, each of which were deficient in one of the 4 main enzymes that convert omega-3s to active metabolites (COX 1 or 2, or LOX 5 or 12/15). Retinopathy was then induced by oxygen exposure.

Results

The research team found that protection against retinopathy required the 5-LOX enzyme. Specifically, the protective effect was due to 5-LOX oxidation of DHA to the metabolite 4-HDHA (4-hydroxy-DHA).

4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis.

This action was independent of 4-HDHA’s anti-inflammatory effects. Instead, 4-HDHA worked by activating PPAR gamma, a transcription factor that regulates the expression of genes.

In addition, the investigators found significant concentrations of 4-HDHA in healthy human subjects, suggesting that their findings may apply to the way omega-3s block angiogenesis in humans.

The fact that COX 1 and 2 were not involved in inhibiting angiogenesis suggests that COX inhibitors such as aspirin and ibuprofen can be used without negating the beneficial effect of dietary omega-3s.

In contrast, clinical use of 5-LOX inhibitors (e.g. the drug zileuton) in patients at risk of ocular neovascular disease warrants closer investigation in light of these findings.

This new information about omega-3s could make them a promising new treatment option considering that the monthly cost of omega-3 supplementation is a fraction of the up to $4,000 cost per month of anti-VEGF therapy.

Reference

1. Sapieha P,et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of w-3 polyunsaturated fatty acids. Sci Transl Med 3, 69ra12 (2011).