Abstract
Retinal hyperpermeability and subsequent macular edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid metabolites, in particular 12/15-lipoxygenase (LOX)-derived metabolites, in this process. LC/MS lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only significantly increased metabolite (2.4 ± 0.4-fold, P = 0.0004) by high glucose (30 mM) treatment. In the presence of arachidonic acid, additional eicosanoids generated by 12/15-LOX, including 12- and 11-HETEs, were significantly increased. Fluorescein angiography and retinal albumin leakage showed a significant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared with diabetic WT mice. Our previous studies demonstrated the potential role of NADPH oxidase in mediating the permeability effect of 12- and 15-HETEs, therefore we tested the impact of intraocular injection of 12-HETE in mice lacking the catalytic subunit of NADPH oxidase (NOX2). The permeability effect of 12-HETE was significantly reduced in NOX2 -/- mice compared with the WT mice. In vitro experiments also showed that 15-HETE induced HREC migration and tube formation in a NOX-dependent manner. Taken together our data suggest that 12/15-LOX is implicated in DR via a NOX-dependent mechanism.
Original language | English (US) |
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Pages (from-to) | 599-611 |
Number of pages | 13 |
Journal | Journal of Lipid Research |
Volume | 56 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2015 |
Keywords
- 12-and 15-HETEs
- Bioactive lipids
- Diabetic retinopathy
- Lipoxygenase
- Reduced nicotinamide adenine dinucleotide phosphate oxidase
- Retinal inflammation
- Retinal vascular leakage
ASJC Scopus subject areas
- Biochemistry
- Endocrinology
- Cell Biology