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

Journal of Lipid Research (Mar 2015)

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

Affiliations

Ahmed S. Ibrahim: Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA; Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA; Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
Sally Elshafey: Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA
Hassan Sellak: Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA
Khaled A. Hussein: Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA; Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA
Mohamed El-Sherbiny: Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA; Department of Anatomy, Faculty of Medicine,Mansoura University, Mansoura, Egypt
Mohammed Abdelsaid: Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA
Nasser Rizk: Biomedical Science Program, Faculty of Science, Qatar University, Doha, Qatar
Selina Beasley: Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA; Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA
Amany M. Tawfik: Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA; Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA; Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA
Sylvia B. Smith: Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA; Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA
Mohamed Al-Shabrawey: To whom correspondence should be addressed; Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA; Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA; Department of Anatomy, Faculty of Medicine,Mansoura University, Mansoura, Egypt; Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA

Journal volume & issue: Vol. 56, no. 3
pp. 599 – 611

Abstract

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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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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