The Role of Epoxygenated Fatty Acids in Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is the leading cause of blindness in working age Americans. The early stages of DR pathogenesis include chronic inflammation, which can eventually lead to the development of later stages of the disease characterized by pathologic pre-retinal neovascularization. The first goal of this dissertation was to determine diabetes-relevant culture conditions for which to test the effect of a novel class of anti-inflammatory lipids, the epoxygenated fatty acids. Epoxygenated fatty acids of the epoxyeicosatrienoic acid (EET) family and epoxydocosapentaenoic acid (EDP) family are generated by cytochrome P450 epoxygenase enzymes. EET and EDP have been shown to be anti-inflammatory, but their levels are limited by the hydrolysis to diol products by the soluble epoxide hydrolase enzyme (sEH). Thus, the second goal of this dissertation was to determine whether restoration of epoxide levels through exogenous addition and inhibition of their metabolism by sEH was able to inhibit retinal vascular inflammation. However, EETs have been shown to exert pro-angiogenic activities, which would be contraindicated for the late stages of DR. Therefore, the final goal was to determine whether EETs were involved in hypoxia-induced retinal neovascularization.