Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization.
Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization.
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DOI：
10.1016/j.redox.2014.01.023
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发表时间：
2014
期刊：
影响因子：
11.4
通讯作者：
Qiao X
中科院分区：
文献类型：
--
作者：
Li Y;Liu X;Zhou T;Kelley MR;Edwards P;Gao H;Qiao X
目前通过靶向一种分子治疗年龄相关性黄斑变性（AMD）的有效性由于其多因素性质和异质性病理而受到限制。针对AMD发病机制中的多种信号通路或病理组分的治疗策略正在研究中，以获得更好的临床结果。抑制脱嘌呤核酸内切酶1/氧化还原因子-1（APE 1）的氧化还原功能可抑制内皮血管生成，促进神经细胞恢复，从而可能成为AMD的潜在治疗方法。在本研究中，我们首次发现，一种小分子化合物E3330的APE 1氧化还原功能的特异性抑制剂调节视网膜色素上皮（RPE）细胞对氧化应激的反应。E3330可显著阻断亚致死剂量氧化低密度脂蛋白（oxLDL）诱导的RPE细胞增殖下降和衰老进程。同时，E3330还能显著减少RPE细胞内活性氧（ROS）的积聚，下调单核细胞趋化蛋白-1（MCP-1）和血管内皮生长因子（VEGF）的产生，并降低核因子-κB（NF-κB）p65的水平。一组应激和毒性反应转录因子被oxLDL显著上调，E3330恢复了这些转录因子，包括Nrf 2/Nrf 1、p53、NF-κB、HIF 1、CBF/NF-Y/YY 1和MTF-1。此外，单次玻璃体内注射E3330有效地减少了小鼠眼中激光诱导的脉络膜新生血管（CNV）的进展。这些数据表明，E3330有效地挽救了体外氧化应激诱导的RPE衰老和功能障碍的多个方面，并减轻了体内激光诱导的RPE-Bruch膜复合物的损伤。连同其先前确定的抗血管生成和神经保护益处，E3330被暗示用于AMD治疗的潜在用途。用E3330特异性抑制APE 1/Ref-氧化还原功能可阻断oxLDL诱导的RPE增殖下降和衰老样表型进展。E3330可抑制RPE细胞内ROS的生成，下调MCP-1和VEGF的表达，降低核NF-κB p65的表达。E3330可抑制oxLDL诱导的RPE细胞氧化还原敏感性转录因子Nrf 2/Nrf 1、p53、NF-κB、HIF 1、CBF/NF-Y/YY 1和MTF-1的表达。玻璃体内注射E3330可明显降低激光诱导的小鼠眼CNV。E3330对于AMD的管理来说具有巨大的潜力。
The effectiveness of current treatment for age related macular degeneration (AMD) by targeting one molecule is limited due to its multifactorial nature and heterogeneous pathologies. Treatment strategy to target multiple signaling pathways or pathological components in AMD pathogenesis is under investigation for better clinical outcome. Inhibition of the redox function of apurinic endonuclease 1/redox factor-1 (APE1) was found to suppress endothelial angiogenesis and promote neuronal cell recovery, thereby may serve as a potential treatment for AMD. In the current study, we for the first time have found that a specific inhibitor of APE1 redox function by a small molecule compound E3330 regulates retinal pigment epithelium (RPEs) cell response to oxidative stress. E3330 significantly blocked sub-lethal doses of oxidized low density lipoprotein (oxLDL) induced proliferation decline and senescence advancement of RPEs. At the same time, E3330 remarkably decreased the accumulation of intracellular reactive oxygen species (ROS) and down-regulated the productions of monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF), as well as attenuated the level of nuclear factor-κB (NF-κB) p65 in RPEs. A panel of stress and toxicity responsive transcription factors that were significantly upregulated by oxLDL was restored by E3330, including Nrf2/Nrf1, p53, NF-κB, HIF1, CBF/NF-Y/YY1, and MTF-1. Further, a single intravitreal injection of E3330 effectively reduced the progression of laser-induced choroidal neovascularization (CNV) in mouse eyes. These data revealed that E3330 effectively rescued RPEs from oxidative stress induced senescence and dysfunctions in multiple aspects in vitro, and attenuated laser-induced damages to RPE–Bruch׳s membrane complex in vivo. Together with its previously established anti-angiogenic and neuroprotection benefits, E3330 is implicated for potential use for AMD treatment. Specific inhibition of APE1/Ref- redox function with E3330 blocked RPE proliferation decline and senescence-like phenotype advancement induced by oxLDL. E3330 suppressed intracellular ROS, down-regulated the MCP-1 and VEGF production, and reduced nuclear NF-κB p65 in RPEs. E3330 repressed the redox sensitive transcription factors Nrf2/Nrf1, p53, NF-κB, HIF1, CBF/NF-Y/YY1, and MTF-1 that stimulated by oxLDL in RPEs. Intravitreal injection of E3330 markedly reduced the laser-induced CNV in mouse eyes. E3330 holds great potential for the management of AMD.
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影响因子：
1.8
作者：
Jiang, Aihua;Gao, Hua;Kelley, Mark R.;Qiao, Xiaoxi
通讯作者：
Qiao, Xiaoxi
影响因子：
3.3
作者：
Diebold I;Petry A;Hess J;Görlach A
通讯作者：
Görlach A
影响因子：
4.4
作者：
Bhattacharya, Sujoy;Chaum, Edward;Johnson, Leonard R.
通讯作者：
Johnson, Leonard R.
影响因子：
10.5
作者：
Jayaraman, L;Murthy, KGK;Prives, C
通讯作者：
Prives, C
DOI：
10.1161/01.atv.0000258979.92828.bc
发表时间：
2007-04-01
影响因子：
8.7
作者：
Bonello, Steve;Zahringer, Christian;Goerlach, Agnes
通讯作者：
Goerlach, Agnes