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AuthorOthman, Amira
AuthorAhmad, Saif
AuthorMegyerdi, Sylvia
AuthorMussell, Rene
AuthorChoksi, Karishma
AuthorMaddipati, Krishna Rao
AuthorElmarakby, Ahmed
AuthorRizk, Nasser
AuthorAl-Shabrawey, Mohamed
Available date2016-03-31T14:00:59Z
Publication Date2013-02
Publication NamePLoS ONE
CitationOthman A, Ahmad S, Megyerdi S, Mussell R, Choksi K, Maddipati KR, et al. (2013) 12/15-Lipoxygenase-Derived Lipid Metabolites Induce Retinal Endothelial Cell Barrier Dysfunction: Contribution of NADPH Oxidase. PLoS ONE 8(2): e57254.
ISSN1932-6203
URIhttp://dx.doi.org/10.1371/journal.pone.0057254
URIhttp://hdl.handle.net/10576/4307
AbstractThe purpose of the current study was to evaluate the effect of 12/15- lipoxygenase (12/15-LOX) metabolites on retinal endothelial cell (REC) barrier function. FITC-dextran flux across the REC monolayers and electrical cell-substrate impedance sensing (ECIS) were used to evaluate the effect of 12- and 15-hydroxyeicosatetreanoic acids (HETE) on REC permeability and transcellular electrical resistance (TER). Effect of 12- or 15-HETE on the levels of zonula occludens protein 1 (ZO-1), reactive oxygen species (ROS), NOX2, pVEGF-R2 and pSHP1 was examined in the presence or absence of inhibitors of NADPH oxidase. In vivo studies were performed using Ins2Akita mice treated with or without the 12/15-LOX inhibitor baicalein. Levels of HETE and inflammatory mediators were examined by LC/MS and Multiplex Immunoassay respectively. ROS generation and NOX2 expression were also measured in mice retinas. 12- and 15- HETE significantly increased permeability and reduced TER and ZO-1expression in REC. VEGF-R2 inhibitor reduced the permeability effect of 12-HETE. Treatment of REC with HETE also increased ROS generation and expression of NOX2 and pVEGF-R2 and decreased pSHP1 expression. Treatment of diabetic mice with baicalein significantly decreased retinal HETE, ICAM-1, VCAM-1, IL-6, ROS generation, and NOX2 expression. Baicalein also reduced pVEGF-R2 while restored pSHP1 levels in diabetic retina. Our findings suggest that 12/15-LOX contributes to vascular hyperpermeability during DR via NADPH oxidase dependent mechanism which involves suppression of protein tyrosine phosphatase and activation of VEGF-R2 signal pathway.
SponsorQatar National Research Fund (NPRP 4 - 1046 - 3 -284), American Heart Association (AHA00104) and Vision Discovery Institute (VDI002010) and Bridge Fund (BFP00018) from the Georgia Health Sciences University.
Languageen
PublisherPublic Library of Science
SubjectDiabetes mellitus
SubjectRetina
SubjectInflammation
SubjectEndothelial cells
SubjectLipid metabolism
SubjectMouse models
SubjectVascular permeability
SubjectMetabolites
Title12/15-Lipoxygenase-Derived Lipid Metabolites Induce Retinal Endothelial Cell Barrier Dysfunction: Contribution of NADPH Oxidase
TypeArticle
Issue Number2
Volume Number8


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