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首页> 外文期刊>Journal of cellular physiology. >Thrombospondin-1 mediates Rho-kinase inhibitor-induced increase in outflow-facility
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Thrombospondin-1 mediates Rho-kinase inhibitor-induced increase in outflow-facility

机译：血小板反应蛋白- 1介导Rho-kinaseinhibitor-induced增加房水流畅

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Rho-kinase (ROCK) inhibitors, a novel class of anti-glaucoma agents, act by increasing the aqueous humor outflow through the conventional trabecular mesh-work pathway. However, the downstream signaling consequences of the ROCK inhibitor are not completely understood. Our data show that Y39983, a selective ROCK inhibitor, could induce filamentous actin remodeling, reduced cell motility (as measured by cell migration), and transepithelial resistance in primary human TM (hTM) cells. After 2 days Y39983 treatment of hTM cells, a proteomic study identified 20 proteins whose expression was significantly altered. Pathway analysis of those proteins revealed the involvement of the p53 pathway, integrin signaling pathway, and cytoskeletal pathway regulation by Rho GTPase. Thrombospondin-1 (TSP1), a matricellular protein that is increased in glaucoma patients, was down-regulated fivefold following Y39983 treatment. More importantly, both TSP1 antagonist leucine-serine-lysine-leucine (LSKL) and small interfering RNA (siRNA) reduced TSP1 gene and protein expressions as well as hTM cell migration. In the presence of Y39983, no further inhibition of cell migration resulted after LSKL and TSP1 siRNA knockdown. Likewise, LSKL triggered a dose-dependent increase in outflow facility in ex vivo mouse eyes, to a similar extent as Y39983 (83.8% increase by Y39983 vs. 71.2% increase by LSKL at 50 uM). There were no additive effects with simultaneous treatment with LSKL and Y39983, supporting the notion that the effects of ROCK inhibition were mediated by TSP1.
机译：Rho-kinase(岩石)抑制剂,小说类的anti-glaucoma代理,通过增加通过传统的房水流出小梁mesh-work途径。下游信号影响的岩石抑制剂并不是完全理解。表明,Y39983选择性抑制剂,可能引起丝状肌动蛋白重构,减少细胞运动性(以细胞迁移),transepithelial阻力主要的人类TM (hTM)细胞。治疗hTM细胞,蛋白质组学的研究确定20蛋白质的表达显著改变。蛋白质p53的参与通路、信号转导通路和细胞骨架由ρGTPase通路调节。血小板反应蛋白- 1(常会)matricellular蛋白质在青光眼患者增加下调了5倍后Y39983治疗。leucine-serine-lysine-leucine (LSKL)和小核RNA常会基因和减少细胞蛋白表达以及hTM迁移。LSKL后抑制细胞迁移的结果和常会siRNA击倒。引发了流出的增加存在剂量依赖的相关性在体外老鼠的眼睛,类似程度上增加Y39983 Y39983 (83.8% vs。通过LSKL 50嗯)增长71.2%。添加剂的影响同时治疗LSKL Y39983,支持的观点影响岩石的抑制被常会介导。

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