A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase
<p dir="ltr">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 sc...
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2015
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| _version_ | 1864513511376289792 |
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| author | Ahmed S. Ibrahim (10049522) |
| author2 | Sally Elshafey (18806887) Hassan Sellak (842314) Khaled A. Hussein (18806890) Mohamed El-Sherbiny (8830880) Mohammed Abdelsaid (6184889) Nasser Rizk (380137) Selina Beasley (18806893) Amany M. Tawfik (18806896) Sylvia B. Smith (7435550) Mohamed Al-Shabrawey (380138) |
| author2_role | author author author author author author author author author author |
| author_facet | Ahmed S. Ibrahim (10049522) Sally Elshafey (18806887) Hassan Sellak (842314) Khaled A. Hussein (18806890) Mohamed El-Sherbiny (8830880) Mohammed Abdelsaid (6184889) Nasser Rizk (380137) Selina Beasley (18806893) Amany M. Tawfik (18806896) Sylvia B. Smith (7435550) Mohamed Al-Shabrawey (380138) |
| author_role | author |
| dc.creator.none.fl_str_mv | Ahmed S. Ibrahim (10049522) Sally Elshafey (18806887) Hassan Sellak (842314) Khaled A. Hussein (18806890) Mohamed El-Sherbiny (8830880) Mohammed Abdelsaid (6184889) Nasser Rizk (380137) Selina Beasley (18806893) Amany M. Tawfik (18806896) Sylvia B. Smith (7435550) Mohamed Al-Shabrawey (380138) |
| dc.date.none.fl_str_mv | 2015-03-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1194/jlr.m056069 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/A_lipidomic_screen_of_hyperglycemia-treated_HRECs_links_12_15-Lipoxygenase_to_microvascular_dysfunction_during_diabetic_retinopathy_via_NADPH_oxidase/26018263 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics diabetic retinopathy 12- and 15-HETEs retinal vascular leakage reduced nicotinamide adenine dinucleotide phosphate oxidase retinal inflammation ipoxygenase bioactive lipids |
| dc.title.none.fl_str_mv | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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, <i>P</i> = 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<sup>−/−</sup> 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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Lipid Research<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1194/jlr.m056069" target="_blank">https://dx.doi.org/10.1194/jlr.m056069</a></p><p dir="ltr">Additional institutions affiliated with: College of Science - QU (1977-2004/2005), College of Arts and Sciences - QU (2004/05-2016)</p><p><br></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_33ea3cc74708916fe74b6afa7d2258c2 |
| identifier_str_mv | 10.1194/jlr.m056069 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26018263 |
| publishDate | 2015 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidaseAhmed S. Ibrahim (10049522)Sally Elshafey (18806887)Hassan Sellak (842314)Khaled A. Hussein (18806890)Mohamed El-Sherbiny (8830880)Mohammed Abdelsaid (6184889)Nasser Rizk (380137)Selina Beasley (18806893)Amany M. Tawfik (18806896)Sylvia B. Smith (7435550)Mohamed Al-Shabrawey (380138)Biomedical and clinical sciencesClinical sciencesMedical biochemistry and metabolomicsdiabetic retinopathy12- and 15-HETEsretinal vascular leakagereduced nicotinamide adenine dinucleotide phosphate oxidaseretinal inflammationipoxygenasebioactive lipids<p dir="ltr">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, <i>P</i> = 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<sup>−/−</sup> 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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Lipid Research<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1194/jlr.m056069" target="_blank">https://dx.doi.org/10.1194/jlr.m056069</a></p><p dir="ltr">Additional institutions affiliated with: College of Science - QU (1977-2004/2005), College of Arts and Sciences - QU (2004/05-2016)</p><p><br></p>2015-03-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1194/jlr.m056069https://figshare.com/articles/journal_contribution/A_lipidomic_screen_of_hyperglycemia-treated_HRECs_links_12_15-Lipoxygenase_to_microvascular_dysfunction_during_diabetic_retinopathy_via_NADPH_oxidase/26018263CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/260182632015-03-01T00:00:00Z |
| spellingShingle | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase Ahmed S. Ibrahim (10049522) Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics diabetic retinopathy 12- and 15-HETEs retinal vascular leakage reduced nicotinamide adenine dinucleotide phosphate oxidase retinal inflammation ipoxygenase bioactive lipids |
| status_str | publishedVersion |
| title | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| title_full | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| title_fullStr | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| title_full_unstemmed | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| title_short | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| title_sort | A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase |
| topic | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics diabetic retinopathy 12- and 15-HETEs retinal vascular leakage reduced nicotinamide adenine dinucleotide phosphate oxidase retinal inflammation ipoxygenase bioactive lipids |