Loss of vascular cells in the retina of the eye, loss of barrier function in vessels, edema, and a cascade of inflammatory events lead to blindness. The eye generates a dihydroxy metabolite from polyunsaturated fatty acids that initiates pericyte loss and breakdown of the endothelial barrier function in the eye, the scientists said. This leads to vascular edema and ultimately to a proliferation of new blood vessels and loss of vision.
The small molecule which initiates this process is a diol of a long chain poly unsaturated fatty acid produced by sEH, the researchers said. The enzyme converts an anti-inflammatory epoxy fatty acid into the pro inflammatory and in this case, toxic diol. The research team demonstrated this process and the cellular mechanism involved in diabetic mice and in transgenic mice that over-produce the sEH enzyme.
They were able to block the process by inhibiting the sEH enzyme. The expression of the sEH enzyme also increased with severity of diabetic retinopathy in human patients.The expression of the soluble epoxide hydrolase gene was shown to increase in the retinas of human patients with the severity of the disease with non-proliferative diabetic retinopathy. Diabetic eye disease can affect many parts of the eye, including the retina, macula, lens and the optic nerve.
Diabetic retinopathy is the most common diabetic eye disease and a leading cause of adult blindness. Chronically high blood sugar from diabetes damages the tiny blood vessels in the retina, leading to diabetic retinopathy, according to the National Eye Institute (NEI) of the National Institutes of Health. The blood vessels can leak fluid or hemorrhage and distorting vision. The sEH enzyme generates a toxic metabolite, but when the enzyme is inhibited, eye disease is prevented.
Inhibiting the soluble epoxide hydrolase preserves fatty acid epoxides which reduce the late or proliferative stages of diabetic retinopathy and macular degeneration. Research team used the same soluble epoxide hydrolase inhibitors to block production of a pro inflammatory mediator that initiates the early stages of vascular permeability and inflammation of the retina. They discovered that 19,20-dihydroxydocosapentaenoic acid, a product of soluble epoxide hydrolase (sEH) activity, as a key regulator of pericyte loss and endothelial barrier breakdown has brought to light a previously unknown mechanism of action in the induction of diabetic retinopathy.
Inhibition of sEH blocks formation of this degenerative lipid metabolite thereby halting disease progression, which is of vital interest for the potential management of this blinding disease.The diol of the fatty acid linoleate produced by the soluble epoxide hydrolase was highly toxic to cells leading to vascular permeability and sepsis. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, pain and inflammation.
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