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    Increased Expression and Activity of 12-Lipoxygenase in Oxygen-Induced Ischemic Retinopathy and Proliferative Diabetic Retinopathy

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    Authors
    Al-Shabrawey, Mohamed
    Mussell, Rene
    Kahook, Khalid
    Tawfik, Amany
    Eladl, Mohamed
    Sarthy, Vijay
    Nussbaum, Julian
    El-Marakby, Ahmed
    Park, Sun Young
    Gurel, Zafer
    Sheibani, Nader
    Maddipati, Krishna Rao
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    Issue Date
    2011-01-21
    URI
    http://hdl.handle.net/10675.2/629
    
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    Abstract
    OBJECTIVE: Arachidonic acid is metabolized by 12-lipoxygenase (12-LOX) to 12-hydroxyeicosatetraenoic acid (12-HETE) and has an important role in the regulation of angiogenesis and endothelial cell proliferation and migration. The goal of this study was to investigate whether 12-LOX plays a role in retinal neovascularization (NV).
    RESEARCH DESIGN AND METHODS: Experiments were performed using retinas from a murine model of oxygen-induced ischemic retinopathy (OIR) that was treated with and without the LOX pathway inhibitor, baicalein, or lacking 12-LOX. We also analyzed vitreous samples from patients with and without proliferative diabetic retinopathy (PDR). Western blotting and RT-PCR were used to assess the expression of 12-LOX, vascular endothelial growth factor (VEGF), and pigment epitheliumâ derived factor (PEDF). Liquid chromatographyâ mass spectrometry was used to assess the amounts of HETEs in the murine retina and human vitreous samples. The effects of 12-HETE on VEGF and PEDF expression were evaluated in Müller cells (rMCs), primary mouse retinal pigment epithelial cells, and astrocytes.
    RESULTS: Retinal NV during OIR was associated with increased 12-LOX expression and 12-, 15-, and 5-HETE production. The amounts of HETEs also were significantly higher in the vitreous of diabetic patients with PDR. Retinal NV was markedly abrogated in mice treated with baicalein or mice lacking 12-LOX. This was associated with decreased VEGF expression and restoration of PEDF levels. PEDF expression was reduced in 12-HETEâ treated rMCs, astrocytes, and the retinal pigment epithelium. Only rMCs and astrocytes showed increased VEGF expression by 12-HETE.
    CONCLUSIONS: 12-LOX and its product HETE are important regulators of retinal NV through modulation of VEGF and PEDF expression and could provide a new therapeutic target to prevent and treat ischemic retinopathy.
    Citation
    Diabetes. 2011 Feb 21; 60(2):614-624
    ae974a485f413a2113503eed53cd6c53
    10.2337/db10-0008
    Scopus Count
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    Department of Oral Biology & Diagnostic Sciences: Faculty Research and Publications

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