title: A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor.
abstract: Lipofuscin contains fluorophores, which represent a biomarker for cellular aging. Although it remains unsubstantiated clinically, experimental results support that the accumulation of lipofuscin is related to an increased risk of choroidal neovascularization due to age-related macular degeneration, a leading cause of legal blindness. Here, we report that a major lipofuscin component, A2E, activates the retinoic acid receptor (RAR). In vitro experiments using luciferase reporter assay, competitional binding assay, analysis of target genes, and chromatin immunoprecipitation (ChIP) assay strongly suggest that A2E is a bona fide ligand for RAR and induces sustained activation of RAR target genes. A2E-induced vascular endothelial growth factor (VEGF) expression in a human retinal pigment epithelial cell line (ARPE-19) and RAR antagonist blocked the up-regulation of VEGF. The conditioned medium of A2E-treated ARPE-19 cells induced tube formation in human umbilical vascular endothelial cells, which was blocked by the RAR antagonist and anti-VEGF antibody. These results suggest that A2E accumulation results in the phenotypic alteration of retinal pigment epithelial cells, predisposing the environment to choroidal neovascularization development. This is mediated through the agonistic function of A2E, at least in part. The results of this study provide a novel potential therapeutic target for this incurable condition.
authors.affiliation: Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Iriyama
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fujiki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Inoue
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takezawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Takeyama
authors.forename: Woo-Dong
authors.initials: WD
authors.lastname: Jang
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yanagi
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008062:Lipofuscin / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010857:Pigment Epithelium of Eye / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000378:metabolism* / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012168:Retinal Pigments / Q000378:metabolism* / Q000494:pharmacology; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); D008024:Ligands; D008062:Lipofuscin; D011726:Pyridinium Compounds; D018168:Receptors, Retinoic Acid; D012168:Retinal Pigments; D012176:Retinoids; D042461:Vascular Endothelial Growth Factor A