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

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.

• Authors: Ahmed S Ibrahim, Amany M Tawfik, Khaled A Hussein, Sally Elshafey, Shanu Markand, Nasser Rizk, Elia J Duh, Sylvia B Smith, Mohamed Al-Shabrawey
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1851 Issue 3 Pg. 290-8 (Mar 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25562624 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• 12-15-lipoxygenase
• Acetophenones
• Eye Proteins
• Hydroxyeicosatetraenoic Acids
• IL6 protein, human
• Interleukin-6
• Membrane Glycoproteins
• NF-kappa B
• Nerve Growth Factors
• Serpins
• TJP1 protein, human
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• Zonula Occludens-1 Protein
• pigment epithelium-derived factor
• Intercellular Adhesion Molecule-1
• 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
• 15-hydroxy-5,8,11,13-eicosatetraenoic acid
• acetovanillone
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases

Topics

• 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid (antagonists & inhibitors, pharmacology)
• Acetophenones (pharmacology)
• Animals
• Arachidonate 12-Lipoxygenase (genetics, metabolism)
• Arachidonate 15-Lipoxygenase (genetics, metabolism)
• Cells, Cultured
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology)
• Diabetic Retinopathy (drug therapy, genetics, metabolism, pathology)
• Endothelial Cells (drug effects, metabolism, pathology)
• Ependymoglial Cells (drug effects, metabolism, pathology)
• Eye Proteins (pharmacology)
• Gene Expression Regulation
• Humans
• Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, pharmacology)
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Interleukin-6 (genetics, metabolism)
• Intravitreal Injections
• Membrane Glycoproteins (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases (antagonists & inhibitors, genetics, metabolism)
• NF-kappa B (genetics, metabolism)
• Nerve Growth Factors (pharmacology)
• Retina (drug effects, metabolism, pathology)
• Retinal Neovascularization (drug therapy, genetics, metabolism, pathology)
• Serpins (pharmacology)
• Signal Transduction
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Vascular Cell Adhesion Molecule-1 (genetics, metabolism)
• Zonula Occludens-1 Protein (genetics, metabolism)