Elizabeth Moran1, Lexi Ding2, Zhongxiao Wang3, Rui Cheng3, Qian Chen3, Robert Moore3, Yusuke Takahashi4, Jian-xing Ma5. 1. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States. 2. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China. 3. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States. 4. Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States. 5. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Abstract
PURPOSE: Previous studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPARα) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARα's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS: For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARα knockout (PPARα(-/-)) mice were exposed to 75% O₂ from postnatal day 7 (P7) to P12 and treated with the PPARα agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl₂ to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS: Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARα(-/-) OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARα overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-α (HIF-1α) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARα(-/-) mice. CONCLUSIONS: Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1α/Nox 4 and consequently alleviation of oxidative stress. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
PURPOSE: Previous studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPARα) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARα's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS: For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARα knockout (PPARα(-/-)) mice were exposed to 75% O₂ from postnatal day 7 (P7) to P12 and treated with the PPARα agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl₂ to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS:Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARα(-/-) OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARα overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-α (HIF-1α) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARα(-/-) mice. CONCLUSIONS:Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1α/Nox 4 and consequently alleviation of oxidative stress. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Authors: Yang Hu; Ying Chen; Lexi Ding; Xuemin He; Yusuke Takahashi; Yang Gao; Wei Shen; Rui Cheng; Qian Chen; Xiaoping Qi; Michael E Boulton; Jian-xing Ma Journal: Proc Natl Acad Sci U S A Date: 2013-09-03 Impact factor: 11.205
Authors: Kim A Radermacher; Kirstin Wingler; Friederike Langhauser; Sebastian Altenhöfer; Pamela Kleikers; J J Rob Hermans; Martin Hrabě de Angelis; Christoph Kleinschnitz; Harald H H W Schmidt Journal: Antioxid Redox Signal Date: 2012-10-16 Impact factor: 8.401
Authors: Mariana I Holubiec; Juan I Romero; Juan Suárez; Manuel Portavella; Emilio Fernández-Espejo; Eduardo Blanco; Pablo Galeano; Fernando Rodríguez de Fonseca Journal: Psychopharmacology (Berl) Date: 2018-07-29 Impact factor: 4.530
Authors: Paulina Escandon; Brenda Vasini; Amy E Whelchel; Sarah E Nicholas; H Greg Matlock; Jian-Xing Ma; Dimitrios Karamichos Journal: Exp Eye Res Date: 2021-05-16 Impact factor: 3.770
Authors: Eduardo Blanco; Pablo Galeano; Mariana I Holubiec; Juan I Romero; Tamara Logica; Patricia Rivera; Francisco J Pavón; Juan Suarez; Francisco Capani; Fernando Rodríguez de Fonseca Journal: Front Neuroanat Date: 2015-11-03 Impact factor: 3.856