VIP Stabilizes the Cytoskeleton of Schlemm's Canal Endothelia via Reducing Caspase-3 Mediated ZO-1 Endolysosomal Degradation.
VIP Stabilizes the Cytoskeleton of Schlemm's Canal Endothelia via Reducing Caspase-3 Mediated ZO-1 Endolysosomal Degradation.
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VIP 通过减少 Caspase-3 介导的 ZO-1 内溶酶体降解来稳定施累姆氏管内皮细胞的细胞骨架
DOI：
10.1155/2021/9397960
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发表时间：
2021
影响因子：
--
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Lou X;Mou Q;Zhao B;Huang J;Yao K;Luo Z;Ye M;Hu Y;Duan Q;Li X;Wen Z;Chen Z;Zhang H;Zhao Y
在青光眼眼中，主要的房水（AH）外流途径会因微环境产生的累积氧化应激、血管调节异常以及衰老而受损，进而导致外流阻力增加和眼压升高。施莱姆管（SC）是主要房水外流途径的最终滤过屏障。本研究旨在探究血管活性肠肽（VIP）是否可通过稳定SC中的紧密连接蛋白1（ZO - 1）来对细胞骨架进行调控。
采用巩膜上静脉烧灼诱导的慢性高眼压（COH）模型，并局部应用VIP进行处理。在COH模型中检测连接结构的超微结构、ZO - 1水平以及SC内壁对异硫氰酸荧光素 - 葡聚糖（70 kDa）的通透性。研究人脐静脉内皮细胞（HUVECs）和人胚肾293细胞中丝状肌动蛋白（F - actin）的分布、F / G - 肌动蛋白比率以及ZO - 1的降解途径。
SC外壁的ZO - 1含量少于内壁。COH导致大鼠SC内壁连接结构破坏、ZO - 1减少以及对异硫氰酸荧光素 - 葡聚糖的通透性增加。ZO - 1在维持F / G - 肌动蛋白比率和F - actin分布方面起着至关重要的作用。VIP处理减轻了与COH或过氧化氢（H₂O₂）诱导的氧化损伤相关的ZO - 1下调。在H₂O₂刺激的HUVECs中，半胱天冬酶 - 3抑制剂可防止ZO - 1破坏。半胱天冬酶 - 3激活促进了ZO - 1的内溶酶体降解。此外，在VIP + H₂O₂处理的细胞中，半胱天冬酶 - 3激活减少且细胞骨架重新分布。敲低ZO - 1或过表达半胱天冬酶 - 3可阻断VIP对细胞骨架的作用。
本研究深入揭示了VIP在稳定肌动蛋白细胞骨架与细胞连接之间相互作用中的作用，可能为青光眼治疗提供一种有前景的靶向策略。
Objectives In glaucomatous eyes, the main aqueous humor (AH) outflow pathway is damaged by accumulated oxidative stress arising from the microenvironment, vascular dysregulation, and aging, which results in increased outflow resistance and ocular hypertension. Schlemm's canal (SC) serves as the final filtration barrier of the main AH outflow pathway. The present study is aimed at investigating the possible regulation of vasoactive intestinal peptide (VIP) on the cytoskeleton by stabilizing ZO-1 in SC. Methods Model of chronic ocular hypertension (COH) induced by episcleral venous cauterization was treated with topical VIP. The ultrastructure of junctions, ZO-1 levels, and permeability of the SC inner wall to FITC-dextran (70 kDa) were detected in the COH models. The F-actin distribution, F/G-actin ratio, and ZO-1 degradation pathway in human umbilical vein endothelial cells (HUVECs) and HEK 293 cells were investigated. Results ZO-1 in the outer wall of the SC was less than that in the inner wall. COH elicited junction disruption, ZO-1 reduction, and increased permeability of the SC inner wall to FITC-dextran in rats. ZO-1 plays an essential role in maintaining the F/G-actin ratio and F-actin distribution. VIP treatment attenuated the downregulation of ZO-1 associated with COH or H2O2-induced oxidative damage. In H2O2-stimulated HUVECs, the caspase-3 inhibitor prevents ZO-1 disruption. Caspase-3 activation promoted endolysosomal degradation of ZO-1. Furthermore, a decrease in caspase-3 activation and cytoskeleton redistribution was demonstrated in VIP + H2O2-treated cells. The knockdown of ZO-1 or the overexpression of caspase-3 blocked the effect of VIP on the cytoskeleton. Conclusion This study provides insights into the role of VIP in stabilizing the interaction between the actin cytoskeleton and cell junctions and may provide a promising targeted strategy for glaucoma treatment.
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影响因子：
4.6
作者：
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