Simvastatin Attenuates Glucocorticoid-Induced Human Trabecular Meshwork Cell Dysfunction via YAP/TAZ Inactivation.
Simvastatin Attenuates Glucocorticoid-Induced Human Trabecular Meshwork Cell Dysfunction via YAP/TAZ Inactivation.
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辛伐他汀通过YAP/TAZ失活减弱糖皮质激素引起的人小梁网细胞功能障碍。
DOI：
10.1080/02713683.2023.2206067
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发表时间：
2023-08
影响因子：
2
通讯作者：
中科院分区：
文献类型：
--
作者：
小梁网(TM)受损是青光眼流出阻力增加的主要原因。YAP和带有PDZ结合基序的转录共激活因子(TAZ)是TM细胞/组织功能障碍的潜在介体。此外，最近发现在非眼细胞中，YAP/TAZ的活性受甲氧戊酸途径控制。临床上使用的他汀类药物阻断甲伐他汀级联反应，并被证明可以改善TM细胞的病理生物学；然而，与YAP/TAZ信号的联系尚未被研究。在这项研究中，我们假设辛伐他汀通过YAP/TAZ失活来减轻糖皮质激素诱导的人TM(HTM)细胞功能障碍。原代HTM细胞种植在生物工程细胞外基质(ECM)水凝胶上或包裹在ECM水凝胶中。在没有辛伐他汀或辛伐他汀存在的情况下，地塞米松用于诱导HTM细胞的病理表型。观察YAP/TAZ活性、肌动蛋白细胞骨架结构、磷酸化肌球蛋白轻链水平、水凝胶收缩/僵硬和纤维连接蛋白沉积的变化。辛伐他汀能有效地阻断HTM细胞的病理性YAP/TAZ核定位/活性、肌动蛋白应激纤维形成和肌球蛋白轻链磷酸化。重要的是，辛伐他汀联合治疗显著减弱地塞米松诱导的ECM收缩/僵硬以及纤维连接蛋白的mRNA和蛋白水平。序贯治疗同样有效，但不能与临床使用的Rho激酶抑制药物相匹配。在模拟组织的ECM微环境中，辛伐他汀灭活YAP/TAZ可减轻HTM细胞的病理生理学。我们的数据可能有助于解释，通过间接抑制YAP/TAZ作为一种拟议的调节机制，他汀类药物的使用与青光眼风险的降低之间的关联。
Impairment of the trabecular meshwork (TM) is the principal cause of increased outflow resistance in the glaucomatous eye. Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ) are emerging as potential mediators of TM cell/tissue dysfunction. Furthermore, YAP/TAZ activity was recently found to be controlled by the mevalonate pathway in non-ocular cells. Clinically-used statins block the mevalonate cascade and were shown to improve TM cell pathobiology; yet, the link to YAP/TAZ signaling was not investigated. In this study, we hypothesized that simvastatin attenuates glucocorticoid-induced human TM (HTM) cell dysfunction via YAP/TAZ inactivation. Primary HTM cells were seeded atop or encapsulated within bioengineered extracellular matrix (ECM) hydrogels. Dexamethasone was used to induce a pathologic phenotype in HTM cells in the absence or presence of simvastatin. Changes in YAP/TAZ activity, actin cytoskeletal organization, phospho-myosin light chain levels, hydrogel contraction/stiffness, and fibronectin deposition were assessed. Simvastatin potently blocked pathologic YAP/TAZ nuclear localization/activity, actin stress fiber formation, and myosin light chain phosphorylation in HTM cells. Importantly, simvastatin co-treatment significantly attenuated dexamethasone-induced ECM contraction/stiffening and fibronectin mRNA and protein levels. Sequential treatment was similarly effective but did not match clinically-used Rho kinase inhibition. YAP/TAZ inactivation with simvastatin attenuates HTM cell pathobiology in a tissue-mimetic ECM microenvironment. Our data may help explain the association of statin use with a reduced risk of developing glaucoma via indirect YAP/TAZ inhibition as a proposed regulatory mechanism.
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作者：
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DOI：
10.1016/j.bbrc.2015.09.012
发表时间：
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影响因子：
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