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J. Biol. Chem., Vol. 283, Issue 18, 11947-11953, May 2, 2008

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A2E, a Pigment of the Lipofuscin of Retinal Pigment Epithelial Cells, Is an Endogenous Ligand for Retinoic Acid Receptor^*

Aya Iriyama, Ryoji Fujiki, Yuji Inoue, Hidenori Takahashi, Yasuhiro Tamaki, Shinichiro Takezawa, Kenichi Takeyama, Woo-Dong Jang^¶, Shigeaki Kato, and Yasuo Yanagi¹

From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan, the Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan, and the ^¶Department of Chemistry, College of Science, Yonsei University, Seoul 120-749, Korea

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.

Received for publication, November 1, 2007 , and in revised form, February 12, 2008.

^* This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-3-5800-8660; Fax: 81-3-3817-0798; E-mail: yanagi-tky{at}umin.ac.jp.

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