Inhibition of Histone Deacetylase Protects the Retina from Ischemic Injury
Inhibition of Histone Deacetylase Protects the Retina from Ischemic Injury
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DOI：
10.1167/iovs.09-4538
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发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
Menick, Donald R.
中科院分区：
文献类型：
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作者：
Crosson, Craig E.;Mani, Santhosh K.;Menick, Donald R.
目的.视网膜缺血的发病机制是由一系列涉及基因表达和炎性细胞因子变化的事件引起的。蛋白质乙酰化是调节转录和炎症事件的重要机制。本研究旨在探讨组蛋白去乙酰化酶（HDAC）抑制剂阿司他丁A（TSA）在视网膜缺血模型中的神经保护作用。为了研究HDAC抑制是否可以减少缺血性损伤，在第0、1、2和3天每天两次用TSA（2.5mg/kg腹膜内）处理大鼠。缺血性损伤后7天，使用形态测量和视网膜电图（ERG）分析来评估视网膜结构和功能。Western blot和免疫组化分析用于评估TSA诱导的组蛋白-H3乙酰化和MMP分泌的变化。在溶剂处理的动物中，与对侧反应相比，缺血眼的ERG a波和b波显著降低。此外，这些眼睛的组织学检查显示视网膜内层明显变性。TSA治疗组大鼠缺血眼ERG a波和b波振幅显著增加，视网膜内层形态正常。缺血也增加了视网膜TNF-α的水平，这是由TSA治疗阻断。在星形胶质细胞培养物中，加入TNF-α（10 ng/mL）刺激MMP-1和MMP-3的分泌，TSA（100 nM）可阻断MMP-1和MMP-3的分泌。这些研究提供了抑制HDAC活性可以保护视网膜免受缺血性损伤的第一个证据。这种神经保护反应与视网膜TNF-α表达和信号传导的抑制有关。HDAC抑制剂的使用可能为缺血性视网膜损伤提供新的治疗方法。（Invest Ophthalmol维斯科学。2010;51：3639-3645）DOI：10.1167/iovs.09-4538
PURPOSE. The pathogenesis of retinal ischemia results from a series of events involving changes in gene expression and inflammatory cytokines. Protein acetylation is an essential mechanism in regulating transcriptional and inflammatory events. The purpose of this study was to investigate the neuroprotective action of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in a retinal ischemic model.METHODS. To investigate whether HDAC inhibition can reduce ischemic injury, rats were treated with TSA (2.5 mg/kg intraperitoneally) twice daily on days 0, 1, 2, and 3. Seven days after ischemic injury, morphometric and electroretinographic (ERG) analyses were used to assess retinal structure and function. Western blot and immunohistochemical analyses were used to evaluate TSA-induced changes in histone-H3 acetylation and MMP secretion.RESULTS. In vehicle-treated animals, ERG a- and b-waves from ischemic eyes were significantly reduced compared with contralateral responses. In addition, histologic examination of these eyes revealed significant degeneration of inner retinal layers. In rats treated with TSA, amplitudes of ERG a-and b-waves from ischemic eyes were significantly increased, and normal inner retina morphology was preserved. Ischemia also increased the levels of retinal TNF-alpha, which was blocked by TSA treatment. In astrocyte cultures, the addition of TNF-alpha (10 ng/mL) stimulated the secretion of MMP-1 and MMP-3, which were blocked by TSA (100 nM).CONCLUSIONS. These studies provide the first evidence that suppressing HDAC activity can protect the retina from ischemic injury. This neuroprotective response is associated with the suppression of retinal TNF-alpha expression and signaling. The use of HDAC inhibitors may provide a novel treatment for ischemic retinal injury. (Invest Ophthalmol Vis Sci. 2010;51:3639-3645) DOI: 10.1167/iovs.09-4538