Abstract
Proliferative diabetic retinopathy is a potentially blinding sequela of uncontrolled diabetes that involves a complex interaction of pro-angiogenic and inflammatory pathways. In this study, we compared the levels of pro-angiogenic arachidonic acid-derived mediators in human vitreous humor obtained from eyes with high-risk proliferative diabetic retinopathy versus controls. The results indicated that lipoxygenase and cytochrome P450-derived eicosanoids were elevated (5-HETE, 12-HETE, 20-HETE, and 20-COOH-AA), and there appeared to be no differences in levels measured in eyes with tractional retinal detachments versus those without. These results provide further insight into the pathogenesis of this disease and for the development of future potential therapeutic agents that target arachidonic acid metabolites to treat diabetic retinopathy.
Highlights
Proliferative diabetic retinopathy (PDR) is a sight-threatening condition faced by many diabetic patients [1,2,3,4,5]
Prior to the advent of anti-vascular endothelial growth factor (VEGF) therapy, diabetic retinopathy was commonly treated with corticosteroid-based medications, which act in part by inhibiting phospholipase A2 and the formation of eicosanoids [34]
Diabetic complications not adequately treated with anti-VEGF drugs are often medically treated with pan-retinal photocoagulation (PRP) or intravitreal corticosteroids
Summary
Proliferative diabetic retinopathy (PDR) is a sight-threatening condition faced by many diabetic patients [1,2,3,4,5]. Prior research has confirmed elevations of VEGF in vitreous samples in diabetic retinopathy [10], with VEGF increasing retinal endothelial permeability [11]. Theof current view concerning the pathogenesis of PDR involves intraocular impetus form prothe action the well-established vascular endothelial growth an factor (VEGF), and toother de-novo aberrant retinal vessels to counteract microvascular ischemia [9,13]. 12-HETE levels have been shown to be elevated creatinine levels, or the degree of proteinuria [33] Both 12-HETE and 15-HETE increase the permeability of murine retinal endothelial cells, a phenomenon reversed by anti-VEGF treatment [11]. Mediators formed from AA in diabetic retinopathy, primarily LOX- and CYP450 derived HETEs, Cytochrome P450 enzymes lead to the formation of 18-19-, and 20-HETE, and stimulates epoxyeicosatrienoic acid (EETs), and dihydroxyeicosatraenoic acid (DiHETEs). VEGF increases 20-HETE production (Figure 1), and blockade of the formation of 20-HETE prevents the angiogenic effects of VEGF [24]. 20-carboxy-arachidonic acid
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