Hanus Jakub, Zhang Hongmei, Chen David H, Zhou Qinbo, Jin Peng, Liu Qinghua, Wang Shusheng
Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Mol Cell Biol. 2015 Jun 1;35(11):1952-63. doi: 10.1128/MCB.00178-15. Epub 2015 Mar 23.
The late stage of dry age-related macular degeneration (AMD), or geographic atrophy (GA), is characterized by extensive retinal pigment epithelial (RPE) cell death, and a cure is not available currently. We have recently demonstrated that RPE cells die from necrosis in response to oxidative stress, providing a potential novel mechanism for RPE death in AMD. In this study, we screened U.S. Food and Drug Administration-approved natural compounds and identified gossypol acetic acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces antioxidative response and inhibits accumulation of excessive reactive oxygen species in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) is found to mediate GAA function in antioxidative response and RPE survival upon oxidative stress. Moreover, Forkhead box O3 transcription factor (FoxO3) is further found to be required for GAA-mediated SESN2 expression and RPE survival. Mechanistically, GAA promotes FoxO3 nuclear translocation and binding to the SESN2 enhancer, which in turn increases its transcriptional activity. Taken together, we have identified GAA as a potent inhibitor of oxidative stress-induced RPE necrosis by regulating the FoxO3/SESN2 pathway. This study may have significant implications in the therapeutics of age-related diseases, especially GA.
干性年龄相关性黄斑变性（AMD）的晚期，即地图样萎缩（GA），其特征是视网膜色素上皮（RPE）细胞广泛死亡，目前尚无治愈方法。我们最近证明，RPE细胞因氧化应激而坏死，这为AMD中RPE细胞死亡提供了一种潜在的新机制。在本研究中，我们筛选了美国食品药品监督管理局批准的天然化合物，并确定醋酸棉酚（GAA）是氧化应激诱导的RPE细胞死亡的有效抑制剂。GAA诱导抗氧化反应并抑制细胞中过量活性氧的积累，从而防止氧化应激诱导的内源性坏死途径的激活。发现Sestrin2（SESN2）在抗氧化反应和氧化应激下RPE细胞存活中介导GAA的功能。此外，进一步发现叉头框O3转录因子（FoxO3）是GAA介导的SESN2表达和RPE细胞存活所必需的。机制上，GAA促进FoxO3核转位并与SESN2增强子结合，进而增加其转录活性。综上所述，我们通过调节FoxO3/SESN2途径确定GAA是氧化应激诱导的RPE坏死的有效抑制剂。本研究可能对年龄相关性疾病，尤其是GA的治疗具有重要意义。
