Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo.
Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo.
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DOI：
10.1016/j.visres.2010.10.008
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发表时间：
2011-01
期刊：
影响因子：
1.8
通讯作者：
Qiao, Xiaoxi
中科院分区：
文献类型：
--
作者：
Jiang, Aihua;Gao, Hua;Kelley, Mark R.;Qiao, Xiaoxi
关键词：
本研究探讨了APE 1/Ref-1在视网膜中的作用及其作为抑制视网膜血管生成的治疗靶点的潜力。通过Western blot定量APE 1/Ref-1表达。通过用APX 3330（一种APE 1/Ref-1氧化还原活性的小分子抑制剂）处理视网膜血管内皮细胞（RVECs）来检测APE 1/Ref-1氧化还原功能在体外内皮细胞血管生成中的作用。体外方法包括增殖测定、transwell迁移测定、基质胶管形成测定和使用xCELLigence系统的真实的时间细胞分析（RTCA）。通过玻璃体内注射APX 3330处理极低密度脂蛋白（VLDL）受体敲除小鼠（Vldlr−/−），并随后测量视网膜血管瘤样增生（RAP）样新生血管形成一周，进行APE 1/Ref-1的体内功能研究。APE 1/Ref-1在小鼠视网膜、RVEC和周细胞中高度表达。APX 3330（1至10 µM）在体外以剂量依赖性方式抑制RVEC的增殖、迁移和管形成。Vldlr−/− RVEC对APX 3330的敏感性高于野生型RVEC。在Vldlr−/−小鼠中，在RAP样新生血管形成时单次玻璃体内注射APX 3330可显著降低RAP样新生血管形成。APE 1/Ref-1在视网膜血管细胞中表达。APX 3330在体外抑制RVEC血管生成，并显著减少Vldlr−/−小鼠中的RAP样新生血管形成。这些数据支持APE 1/Ref-1氧化还原功能是视网膜血管生成所必需的结论。因此，APE 1/Ref-1可能具有作为治疗新生血管性年龄相关性黄斑变性和其他新生血管性疾病的治疗靶点的潜力。
This study examines the role of APE1/Ref-1 in the retina and its potential as a therapeutic target for inhibiting retinal angiogenesis. APE1/Ref-1 expression was quantified by Western blot. The role of APE1/Ref-1 redox function in endothelial cell in vitro angiogenesis was examined by treating retinal vascular endothelial cells (RVECs) with APX3330, a small molecule inhibitor of APE1/Ref-1 redox activity. In vitro methods included a proliferation assay, a transwell migration assay, a Matrigel tube formation assay, and a Real Time Cell Analysis (RTCA) using the xCELLigence System. In vivo functional studies of APE1/Ref-1 were carried out by treating very low density lipoprotein (VLDL) receptor knockout mice (Vldlr−/−) with intravitreal injection of APX3330, and subsequent measurement of retinal angiomatous proliferation (RAP)-like neovascularization for one week. APE1/Ref-1 was highly expressed in the retina and in RVECs and pericytes in mice. APX3330 (1 to 10 µM) inhibited proliferation, migration and tube formation of RVECs in vitro in a dose-dependent manner. Vldlr−/− RVECs were more sensitive to APX3330 than wild-type RVECs. In Vldlr−/− mice, a single intravitreal injection of APX3330 at the onset of RAP-like neovascularization significantly reduced RAP-like neovascularization development. APE1/Ref-1 is expressed in retinal vascular cells. APX3330 inhibits RVEC angiogenesis in vitro and significantly reduces RAP-like neovascularization in Vldlr−/− mice. These data support the conclusion that APE1/Ref-1 redox function is required for retinal angiogenesis. Thus, APE1/Ref-1 may have potential as a therapeutic target for treating neovascular age-related macular degeneration and other neovascular diseases.
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影响因子：
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作者：
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通讯作者：
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影响因子：
8
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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Linden, R
DOI：
10.1073/pnas.91.1.23
发表时间：
1994-01-04
影响因子：
11.1
作者：
XANTHOUDAKIS, S;MIAO, GG;CURRAN, T
通讯作者：
CURRAN, T