Effects of Thailanstatins on Glucocorticoid Response in Trabecular Meshwork and Steroid-Induced Glaucoma
Effects of Thailanstatins on Glucocorticoid Response in Trabecular Meshwork and Steroid-Induced Glaucoma
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DOI：
10.1167/iovs.12-11480
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发表时间：
2013-05-01
影响因子：
4.4
通讯作者：
Clark, Abbot F.
中科院分区：
文献类型：
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作者：
Jain, Ankur;Liu, Xiangyang;Clark, Abbot F.
目的.眼内压（IOP）升高是青光眼的主要危险因素。小梁网（TM）的各种变化是导致IOP升高的原因。糖皮质激素（GC）增加IOP并介导TM的生化变化，类似于与原发性开角型青光眼（POAG）相关的变化。人群中类固醇反应性存在差异。大约40%的个体显著升高IOP（即，响应者），而其他人则没有（即，无应答者）。与无应答者相比，有应答者发生POAG的风险更高。此外，几乎所有开角型青光眼患者都是类固醇反应者。GC反应性由活性GC受体α（GR α）和选择性剪接显性负调节亚型GR β的相对水平调节。与正常TM细胞相比，青光眼TM细胞株具有较低的GR β-GR α比率，使其对GC更敏感。我们的目的是研究一类特殊的天然产物Thailanstatins（TSTs）在培养的人TM细胞GR选择性剪接和GC反应中的作用。采用定量RT-PCR和Western免疫印迹法研究TSTs对人TM细胞株中GR β-GR α比例的影响。TSTs对地塞米松（DEX）反应性的影响通过GRE-荧光素酶报告活性测定和TM细胞中纤维连接蛋白（FN）的诱导来评估。TSTs增加了TM细胞中GR β-GR α的比例。GR β-GR α比值的增加与DEX介导的FN诱导和GR荧光素酶活性的降低相关。TST调节GR剪接过程以提高GR β水平，从而降低培养的人TM细胞中的GC反应。这些TST或类似化合物可能是新的青光眼治疗剂。
PURPOSE. Elevated intraocular pressure (IOP) is a major risk factor in glaucoma. Various changes in the trabecular meshwork (TM) are responsible for elevated IOP. Glucocorticoids (GCs) increase IOP and mediate biochemical changes in the TM, similar to those associated with primary open-angle glaucoma (POAG). There are differences in steroid responsiveness among the population. Approximately 40% of individuals significantly elevate IOP (i.e., responders) upon GC administration, while others do not (i.e., nonresponders). The responders are at higher risk of developing POAG compared to the nonresponders. In addition, almost all POAG patients are steroid responders. GC responsiveness is regulated by the relative levels of the active GC receptor alpha (GR alpha) and the alternatively spliced dominant negative regulator isoform GR beta. Glaucomatous TM cell strains have a lower GR beta-GR alpha ratio compared to normal TM cells, making them more sensitive to GCs. Our purpose was to investigate the role of a special class of natural products called thailanstatins (TSTs) in GR alternative splicing and GC response in cultured human TM cells.METHODS. Quantitative RT-PCR and Western immunoblotting were used to study the effect of TSTs on GR beta-GR alpha ratios in human TM cell strains. Effects of TSTs on dexamethasone (DEX) responsiveness were assessed by GRE-luciferase reporter activity assay and fibronectin (FN) induction in TM cells.RESULTS. TSTs increased the GR beta-GR alpha ratio in TM cells. Increased GR beta-GR alpha ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity.CONCLUSIONS. TSTs modulate the GR splicing process to enhance GR beta levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.