Iron induced oxidative damage as a potential factor in age-related macular degeneration: The Cogan Lecture
Iron induced oxidative damage as a potential factor in age-related macular degeneration: The Cogan Lecture
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DOI：
10.1167/iovs.06-0568
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发表时间：
2006-11-01
影响因子：
4.4
通讯作者：
Dunaief, Joshua L.
中科院分区：
文献类型：
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作者：
Dunaief, Joshua L.
铁是氧化损伤的有力推动者，其水平随着年龄的增长而增加，可能会加剧与年龄相关的疾病。一些证据表明，铁积累可能是老年性黄斑变性(AMD)的一个因素。与年龄匹配的对照视网膜相比，AMD视网膜的光感受器、RPE和玻璃体中含有更多的铁。遗传性疾病无纤维蛋白原血症所致视网膜铁负荷过重的患者会出现加速的AMD样黄斑病变。铜蓝蛋白及其同系物Hephestin基因敲除导致的视网膜铁负荷过高的小鼠表现出视网膜变性，表现为视网膜下新生血管、RPE脂褐素和RPE亚沉积以及RPE/光感受器死亡。加深对视网膜铁稳态机制的了解可能有助于开发预防铁超载的治疗方法。例如，这里显示了一种系统性铁稳态的调节剂，HFE，在RPE中表达。因此，常见疾病遗传性血色沉着症的患者，通常由HFE突变引起，可能有视网膜铁超载，易患AMD。初步数据表明，铁螯合可以减少小鼠RPE铁超载，保护它们免受退化，这表明铁结合药物有朝一日可能被证明在减少RPE氧化应激和降低AMD进展风险方面有用。
Iron is a potent generator of oxidative damage whose levels increase with age, potentially exacerbating age-related diseases. Several lines of evidence suggest that iron accumulation may be a factor in age-related macular degeneration (AMD). AMD retinas have more iron within the photoreceptors, RPE, and drusen than do age-matched control retinas. Accelerated AMD-like maculopathy develops in patients with retinal iron overload from the hereditary disease aceruloplasminemia. Mice with retinal iron overload resulting from knockout of ceruloplasmin and its homologue hephaestin exhibit retinal degeneration with some features of AMD, including subretinal neovascularization, accumulation of RPE lipofuscin and sub-RPE deposits, and RPE/photoreceptor death. Increased understanding of the mechanisms of retinal iron homeostasis may help in the development of therapies to prevent iron overload. For example, herein it is shown that one regulator of systemic iron homeostasis, HFE, is expressed in the RPE. Thus, patients with the common disease hereditary hemochromatosis, which is often caused by an HFE mutation, may have retinal iron overload predisposing to AMD. Preliminary data suggest that iron chelation can reduce RPE iron overload in mice and protect them from degeneration, suggesting that iron-binding drugs may one day prove useful in reducing RPE oxidative stress and decreasing the risk of AMD progression.