Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy: Implications in retinal neovascularization

Mohamed Al-Shabrawey, Rene Mussell, Khalid Kahook, Amany Mohamed Tawfik, Mohamed Eladl, Vijay Sarthy, Julian J Nussbaum, Ahmed Abdelrazik Elmarakby, Sun Young Park, Zafer Gurel, Nader Sheibani, Krishna Rao Maddipati

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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 epithelium-derived factor (PEDF). Liquid chromatography-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-HETE-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.

Original languageEnglish (US)
Pages (from-to)614-624
Number of pages11
JournalDiabetes
Volume60
Issue number2
DOIs
StatePublished - Feb 1 2011

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Arachidonate 12-Lipoxygenase
Retinal Neovascularization
Hydroxyeicosatetraenoic Acids
Diabetic Retinopathy
Oxygen
Vascular Endothelial Growth Factor A
Astrocytes
Retina
Retinal Pigments
Retinal Pigment Epithelium
Arachidonic Acid
Liquid Chromatography
Cell Movement
Mass Spectrometry
Research Design
Endothelial Cells
Western Blotting
Epithelial Cells
Cell Proliferation
pigment epithelium-derived factor

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy : Implications in retinal neovascularization. / Al-Shabrawey, Mohamed; Mussell, Rene; Kahook, Khalid; Tawfik, Amany Mohamed; Eladl, Mohamed; Sarthy, Vijay; Nussbaum, Julian J; Elmarakby, Ahmed Abdelrazik; Park, Sun Young; Gurel, Zafer; Sheibani, Nader; Maddipati, Krishna Rao.

In: Diabetes, Vol. 60, No. 2, 01.02.2011, p. 614-624.

Research output: Contribution to journalArticle

Al-Shabrawey, Mohamed ; Mussell, Rene ; Kahook, Khalid ; Tawfik, Amany Mohamed ; Eladl, Mohamed ; Sarthy, Vijay ; Nussbaum, Julian J ; Elmarakby, Ahmed Abdelrazik ; Park, Sun Young ; Gurel, Zafer ; Sheibani, Nader ; Maddipati, Krishna Rao. / Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy : Implications in retinal neovascularization. In: Diabetes. 2011 ; Vol. 60, No. 2. pp. 614-624.
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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 epithelium-derived factor (PEDF). Liquid chromatography-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 M{\"u}ller 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-HETE-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.",
author = "Mohamed Al-Shabrawey and Rene Mussell and Khalid Kahook and Tawfik, {Amany Mohamed} and Mohamed Eladl and Vijay Sarthy and Nussbaum, {Julian J} and Elmarakby, {Ahmed Abdelrazik} and Park, {Sun Young} and Zafer Gurel and Nader Sheibani and Maddipati, {Krishna Rao}",
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T1 - Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy

T2 - Implications in retinal neovascularization

AU - Al-Shabrawey, Mohamed

AU - Mussell, Rene

AU - Kahook, Khalid

AU - Tawfik, Amany Mohamed

AU - Eladl, Mohamed

AU - Sarthy, Vijay

AU - Nussbaum, Julian J

AU - Elmarakby, Ahmed Abdelrazik

AU - Park, Sun Young

AU - Gurel, Zafer

AU - Sheibani, Nader

AU - Maddipati, Krishna Rao

PY - 2011/2/1

Y1 - 2011/2/1

N2 - 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 epithelium-derived factor (PEDF). Liquid chromatography-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-HETE-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.

AB - 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 epithelium-derived factor (PEDF). Liquid chromatography-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-HETE-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.

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