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

Journal of Lipid Research

Amany M. Tawfik¹  Hassan Sellak²  Nasser Rizk³  Sally Elshafey³  Mohamed Al-Shabrawey⁴  Mohamed El-Sherbiny⁵  Sylvia B. Smith⁶  Selina Beasley⁷  Khaled A. Hussein⁷  Ahmed S. Ibrahim⁷  Mohammed Abdelsaid⁷ 

[1] Department of Anatomy, Faculty of Medicine,Mansoura University, Mansoura, Egypt;Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA;Biomedical Science Program, Faculty of Science, Qatar University, Doha, Qatar;Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA;Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA;Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA;

关键词: diabetic retinopathy;    12- and 15-HETEs;    retinal vascular leakage;    reduced nicotinamide adenine dinucleotide phosphate oxidase;    retinal inflammation;    lipoxygenase;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown