title: Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation.
abstract: Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORα expression was significantly increased and genetic deficiency of RORα substantially suppressed pathologic retinal neovascularization. Loss of RORα led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. RORα directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of RORα deficiency in vitro and in vivo. Moreover, treatment with a RORα inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low-density lipoprotein receptor (Vldlr)-deficient (Vldlr (-/-) ) mice with spontaneous subretinal neovascularization, whereas a RORα agonist worsened oxygen-induced retinopathy. Our data demonstrate that RORα is a novel regulator of pathologic retinal neovascularization, and RORα inhibition may represent a new way to treat ocular neovascularization.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Chi-Hsiu
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Section on Nutritional Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
authors.forename: John Paul
authors.initials: JP
authors.lastname: SanGiovanni
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Lucy P
authors.initials: LP
authors.lastname: Evans
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Eye Center, University of Freiburg, 79106 Freiburg, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115;
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115; jing.chen@childrens.harvard.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D007249:Inflammation / Q000473:pathology; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009389:Neovascularization, Pathologic; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D012160:Retina / Q000473:pathology*; D015861:Retinal Neovascularization; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008055:Lipids; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D011973:Receptors, LDL; C539739:Rora protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C036053:VLDL receptor; D010100:Oxygen
keywords: RORα; SOCS3; inflammation; neovascularization; retinopathy