Researchers Learn How Certain Omega-3 Fatty Acids May Halt Vision-Robbing Blood Vessel Growth in the Retina

Omega-3 polyunsaturated fatty acids are chemicals found in fish and some nut and vegetable oils that are an essential part of a healthy diet. It is known that fatty acids found in fish oil help to prevent cardiovascular disease. Recently, NEI-supported investigators demonstrated that a byproduct of one of the fatty acids found in fish oil may also keep our eyes healthy.

Proliferative retinopathies are a leading cause of blindness. These diseases, such as diabetic retinopathy and retinopathy of prematurity, are caused by abnormal blood vessel growth, or neovascularization, in the retina, the part of the eye that detects and converts light into electrical signals sent to the brain.

In 2007, a team of researchers published a study, led by Lois Smith, M.D., Ph.D., professor of ophthalmology at Harvard Medical School, Children Hospital Boston, that suggested omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may prevent these diseases. Now Dr. Smith and colleagues show that a byproduct of DHA, called 4-hydroxy-docosahexaenoic acid (4-HDHA), may be the chemical that prevents neovascularization in the retina.

These conclusions are based on studies performed with mice. Briefly exposing mice to air containing high levels of oxygen induces abnormal blood vessel growth in the retina that is reminiscent of the neovascularization seen in many eye diseases. Previously, Dr. Smith and her colleagues showed that feeding mice omega-3 fatty acids reduced abnormal blood vessel growth induced by exposing the animals to high levels of oxygen.

Once eaten, omega-3 fatty acids are converted to healthy byproducts by molecules called enzymes. Each enzyme converts omega-3 fatty acids into a different byproduct. In this study, the investigators searched for the specific byproduct that prevents neovascularization by performing experiments on a variety of mice, each engineered to lack one or more of the enzymes known to convert omega-3 fatty acids into byproducts. Each mouse was fed omega-3 fatty acids and then exposed to high levels of oxygen.

Abnormal blood vessel growth occurred in only one mouse. This mouse lacked the enzyme called 5-lipoxygenase (5-LOX), which normally converts DHA into 4-HDHA. These results indicate that 5-LOX is the enzyme responsible for converting DHA into the anti-neovascular byproduct 4-HDHA.

Interestingly, the researchers found that the conversion of DHA into 4-HDHA did not occur in the retinas of the mice tested, which normally contain lots of DHA. Instead their results suggest that the conversion may occur in immune cells, called leukocytes, which circulate throughout the blood. The researchers showed that human leukocytes can also convert DHA to 4-HDHA, suggesting they may also protect human retinas from neovascularization.

Further experiments supported the idea that 4-HDHA protects the retina from abnormal blood vessel growth. Oxygen exposure increased 4-HDHA levels in retinas from control mice but not in ones from mice lacking the 5-LOX enzyme, suggesting the conversion of DHA to 4-HDHA was a normal, healthy reaction. Moreover experiments performed in petri dishes on isolated blood vessel cells showed that 4-HDHA inhibited them from sprouting finger-like extensions, reminiscent of abnormal blood vessel growth.

The researchers next found that 4-HDHA may prevent abnormal blood vessel growth by binding to and activating a molecule known to regulate gene expression in blood vessel cells called the Peroxisome Proliferator-Activated Receptor (PPAR). PPAR is also a target for some anti-diabetic drugs, such as rosiglitazone and pioglitazone. Previous studies suggest these drugs may prevent neovascularization in the retina, confirming that omega-3 fatty acids may ultimately keep the retina healthy by activating a critical therapeutic target.

The results Dr. Smith and colleagues presented in this study strengthen the idea that eating more fish or taking omega-3 fatty acid dietary supplements may help prevent and treat abnormal blood vessel growth seen in progressive retinopathies, if not related diseases, such as macular degeneration. Current treatments for these diseases, such as laser coagulation or antibody injections into the eye, are invasive and expensive. Dr. Smith notes that because of their excellent safety profile, ease of administration, and low cost, omega-3 therapies are an attractive potential treatment.

The results of this investigation were published in the February 9, 2011 edition of the journal Science Translational Medicine (Sapieha P et al. "5-Lipoxygenase Metabolite 4-HDHA Is a Mediator of the Antiangiogenic Effect of | -3 Polyunsaturated Fatty Acids." Sci Transl Med, February 9, 2011, vol. 3(69), pp. 69ra12).

The study was funded in part by the National Eye Institute (NEI).

Relevant Facts Related to the Study:

• Dietary supplementation with DHA and EPA can reduce the risk of cardiovascular disease and is thought to be beneficial for several other conditions. The NEI is currently funding a five-year, 4,000-participant Age-Related Eye Disease Study (AREDS2) to evaluate the effect of supplementation with DHA and EPA, as well as the carotenoids lutein and zeaxanthin, on the development of cataracts and advanced AMD.
• DHA and EPA are abundant in cold-water fish such as tuna, salmon and mackerel, and are commercially available as dietary supplements.
• Approximately 4.1 million adults 40 years and older in the U.S. have some degree of diabetic retinopathy.
• 14,000-16,000 infants in the U.S. are affected by retinopathy of prematurity.
• Approximately 9 million people in the U.S. have age-related macular degeneration with 1.75 million having significant vision loss from the advanced form of the disease.

This article was co-written by Christopher G. Thomas, Ph.D. and Preethi Chander, Ph.D.

Last Reviewed: July 2011