Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids

Ahmed S. Ibrahim, Amany M. Tawfik, Khaled A. Hussein, Sally Elshafey, Shanu Markand, Nasser Rizk, Elia J. Duh, Sylvia B. Smith, Mohamed Al-Shabrawey

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Abstract

We recently demonstrated that 12/15-lipoxygenase (LOX) derived metabolites, hydroxyeicosatetraenoic acids (HETEs), contribute to diabetic retinopathy (DR) via NADPH oxidase (NOX) and disruption of the balance in retinal levels of the vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). Here, we test whether PEDF ameliorates retinal vascular injury induced by HETEs and the underlying mechanisms. Furthermore, we pursue the causal relationship between LOX-NOX system and regulation of PEDF expression during DR. For these purposes, we used an experimental eye model in which normal mice were injected intravitreally with 12-HETE with/without PEDF. Thereafter, fluorescein angiography (FA) was used to evaluate the vascular leakage, followed by optical coherence tomography (OCT) to assess the presence of angiogenesis. FA and OCT reported an increased vascular leakage and pre-retinal neovascularization, respectively, in response to 12-HETE that were not observed in the PEDF-treated group. Moreover, PEDF significantly attenuated the increased levels of vascular cell and intercellular adhesion molecules, VCAM-1 and ICAM-1, elicited by 12-HETE injection. Accordingly, the direct relationship between HETEs and PEDF has been explored through in-vitro studies using Müller cells (rMCs) and human retinal endothelial cells (HRECs). The results showed that 12- and 15-HETEs triggered the secretion of TNF-α and IL-6, as well as activation of NFκB in rMCs and significantly increased permeability and reduced zonula occludens protein-1 (ZO-1) immunoreactivity in HRECs. All these effects were prevented in PEDF-treated cells. Furthermore, interest in PEDF regulation during DR has been expanded to include NOX system. Retinal PEDF was significantly restored in diabetic mice treated with NOX inhibitor, apocynin, or lacking NOX2 up to 80% of the control level. Collectively, our findings suggest that interfering with LOX-NOX signaling opens up a new direction for treating DR by restoring endogenous PEDF that carries out multilevel vascular protective functions.

Original languageEnglish (US)
Pages (from-to)290-298
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1851
Issue number3
DOIs
StatePublished - Mar 2015

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Eicosanoids
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
NADPH Oxidase
Hydroxyeicosatetraenoic Acids
Diabetic Retinopathy
Arachidonate 15-Lipoxygenase
Blood Vessels
Vascular Cell Adhesion Molecule-1
Fluorescein Angiography
Optical Coherence Tomography
Intercellular Adhesion Molecule-1
12-15-lipoxygenase
pigment epithelium-derived factor
Endothelial Cells
Zonula Occludens-1 Protein
Retinal Neovascularization
Retinal Vessels
Retinal Pigment Epithelium
Vascular System Injuries
Vascular Endothelial Growth Factor A

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids. / Ibrahim, Ahmed S.; Tawfik, Amany M.; Hussein, Khaled A.; Elshafey, Sally; Markand, Shanu; Rizk, Nasser; Duh, Elia J.; Smith, Sylvia B.; Al-Shabrawey, Mohamed.

In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1851, No. 3, 03.2015, p. 290-298.

Research output: Contribution to journalArticle

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AU - Tawfik, Amany M.

AU - Hussein, Khaled A.

AU - Elshafey, Sally

AU - Markand, Shanu

AU - Rizk, Nasser

AU - Duh, Elia J.

AU - Smith, Sylvia B.

AU - Al-Shabrawey, Mohamed

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