A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor
A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor
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DOI：
10.1074/jbc.m708989200
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发表时间：
2008-05-02
影响因子：
4.8
通讯作者：
Yanagi, Yasuo
中科院分区：
文献类型：
--
作者：
Iriyama, Aya;Fujiki, Ryoji;Yanagi, Yasuo
脂褐素含有荧光团，代表细胞衰老的生物标志物。尽管尚未得到临床证实，但实验结果支持脂褐素的积累与年龄相关性黄斑变性引起的脉络膜新生血管风险增加有关，黄斑变性是导致法定失明的主要原因。在这里，我们报道了一种主要的脂褐素成分，A2E，激活视黄酸受体（RAR）。荧光素酶报告基因法、竞争结合法、靶基因分析和染色质免疫沉淀（ChIP）法的体外实验强烈表明，A2E是RAR的真正配体，并诱导RAR靶基因的持续激活。a2e诱导的血管内皮生长因子（VEGF）在人视网膜色素上皮细胞系（ARPE-19）和RAR拮抗剂中的表达阻断了VEGF的上调。a2e处理的ARPE-19细胞条件培养基诱导人脐带血管内皮细胞成管，并被RAR拮抗剂和抗vegf抗体阻断。这些结果表明，A2E的积累导致视网膜色素上皮细胞表型改变，使环境有利于脉络膜新生血管的发育。这至少部分是通过A2E的激动作用介导的。本研究结果为这种不治之症提供了一个新的潜在治疗靶点。
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.