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

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submitted on 2024-07-08, 08:11 and posted on 2024-07-08, 08:13 authored by 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

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.

Other Information

Published in: Journal of Lipid Research
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1194/jlr.m056069

Additional institutions affiliated with: College of Science - QU (1977-2004/2005), College of Arts and Sciences - QU (2004/05-2016)


Funding

Qatar National Research Fund (NPRP 4 - 1046 - 3 - 284), Lipoxygenase Pathway in Retinal Angiogenesis.

History

Language

  • English

Publisher

Elsevier

Publication Year

  • 2015

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Qatar University
  • Qatar University Health - QU
  • College of Arts and Sciences - QU
  • College of Health Sciences - QU HEALTH