A lipidomic screen of hyperglycemia-treated hrecs links 12/15-lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase

Ahmed S. Ibrahim, Sally Elshafey, Hassan Sellak, Khaled A. Hussein, Mohamed El-Sherbiny, Mohammed Abdelsaid, Nasser Rizk, Selina Beasley, Amany M. Tawfik, Sylvia B. Smith, Mohamed Al-Shabrawey

Research output: Contribution to journalArticle

29 Scopus citations

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 languageEnglish (US)
Pages (from-to)599-611
Number of pages13
JournalJournal of Lipid Research
Volume56
Issue number3
DOIs
StatePublished - 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

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