Wu Zhihao, Lauer Thomas W, Sick Anna, Hackett Sean F, Campochiaro Peter A
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
J Biol Chem. 2007 Aug 3;282(31):22414-25. doi: 10.1074/jbc.M702321200. Epub 2007 Jun 8.
Age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly, is a complex disease that results from genetic modifications that increase susceptibility to environmental exposures. Smoking, a major source of oxidative stress, increases the incidence and severity of AMD, and antioxidants slow progression, suggesting that oxidative stress plays a major role. Polymorphisms in the complement factor H (CFH) gene that reduce activity of CFH increase the risk of AMD. In this study we demonstrate an interaction between these two risk factors, because oxidative stress reduces the ability of an inflammatory cytokine, interferon-gamma, to increase CFH expression in retinal pigmented epithelial cells. The interferon-gamma-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter, reduces its binding to STAT1, inhibits STAT1 interaction with the CFH promoter, and reduces expression of CFH. Expression of SIRT1, a mammalian homolog of NAD-dependent protein deacetylase sir2, attenuated FOXO3 recruitment to the CFH regulatory region and reversed the H(2)O(2)-induced repression of CFH gene expression. These data suggest an important interaction between environmental exposure and genetic susceptibility in the pathogenesis of AMD and, by elucidating molecular signaling involved in the interaction, provide potential targets for therapeutic intervention.
年龄相关性黄斑变性（AMD）是老年人严重视力丧失的主要原因，是一种复杂的疾病，由增加对环境暴露易感性的基因改变引起。吸烟作为氧化应激的主要来源，会增加AMD的发病率和严重程度，而抗氧化剂可减缓疾病进展，这表明氧化应激起主要作用。补体因子H（CFH）基因的多态性会降低CFH的活性，从而增加患AMD的风险。在本研究中，我们证明了这两种风险因素之间的相互作用，因为氧化应激会降低炎性细胞因子干扰素-γ在视网膜色素上皮细胞中增加CFH表达的能力。干扰素-γ诱导的CFH增加由STAT1的转录激活介导，而氧化应激对其的抑制作用由FOXO3的乙酰化介导，这会增强FOXO3与CFH启动子的结合，减少其与STAT1的结合，抑制STAT1与CFH启动子的相互作用，并降低CFH的表达。SIRT1是NAD依赖性蛋白脱乙酰酶sir2的哺乳动物同源物，其表达减弱了FOXO3募集到CFH调控区域的能力，并逆转了H₂O₂诱导的CFH基因表达抑制。这些数据表明在AMD发病机制中环境暴露与遗传易感性之间存在重要的相互作用，并且通过阐明相互作用中涉及的分子信号传导，为治疗干预提供了潜在靶点。
