Synthetic Triterpenoids Attenuate Cytotoxic Retinal Injury: Cross-talk between Nrf2 and PI3K/AKT Signaling through Inhibition of the Lipid Phosphatase PTEN
Synthetic Triterpenoids Attenuate Cytotoxic Retinal Injury: Cross-talk between Nrf2 and PI3K/AKT Signaling through Inhibition of the Lipid Phosphatase PTEN
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DOI：
10.1167/iovs.09-3648
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发表时间：
2009-11-01
影响因子：
4.4
通讯作者：
Sporn, Michael
中科院分区：
文献类型：
--
作者：
Pitha-Rowe, Ian;Liby, Karen;Sporn, Michael
目的。表明氧化应激参与年龄相关性黄斑变性发病机制的证据表明，抗氧化疗法可以在预防其进展方面发挥作用。本研究的目的是确定三萜 (TP) 2-cyano-3,12-dioxooleana-1,9-dien-28-oic 酸衍生物（CDDO；CDDO-咪唑烷 [-Im]、CDDO-乙酰胺 [-EA] 和 CDDO-三氟乙酰胺 [-TFEA]）是否具有细胞保护作用，防止氧化和光氧化诱导的细胞损伤，并探讨其分子机制细胞保护。方法。用TP衍生物处理视网膜色素上皮细胞系和视网膜感光细胞系。通过报告基因测定来测量 Nrf2 信号传导的诱导。通过MTT测定对细胞保护进行定量。为了确定 TP 是否具有体内细胞保护作用，用 CDDO-TFEA 预处理 BALB/c 小鼠，并通过光照诱导视网膜变性。为了探索 TP 与 PTEN 的关联，使用了 CDDO 的生物素化衍生物 (CDDO-Bt)。 结果。 CDDO-Im-、-TFEA-或-EA诱导的Nrf2信号传导和TP预处理可保护视网膜细胞系免受氧化剂诱导的细胞死亡。然后在体内检查这些化合物的抗氧化和细胞保护潜力。用 CDDO-TFEA 处理 BALB/c 小鼠，可在视网膜组织中诱导 Nrf2 调节的转录物 glcl 和 trx1，并可保护视网膜免受光氧化损伤。 CDDO-Im 处理导致 AKT 磷酸化。 CDDO-Bt 直接结合 PTEN 活性位点内的半胱氨酸 124，并在体外抑制 PTEN 的脂质磷酸酶活性。因此，AKT 活性的刺激是由 TP 抑制 PTEN 活性介导的。 结论。这些研究强调了 TP 在视网膜细胞保护中的潜力，并表明 PTEN 抑制是细胞保护的一个靶点。 （投资眼科可见科学。2009；50：5339-5347）DOI：10.1167/iovs.09-3648
PURPOSE. Evidence implicating oxidative stress in the pathogenesis of age-related macular degeneration suggests that antioxidant therapy could play a role in preventing its progression. The aim of this study was to determine whether derivatives of the triterpenoid (TP) 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO; CDDO-imidazolide [-Im], CDDO-ethylamide [-EA], and CDDO-trifluoroethylamide [-TFEA]) confer cytoprotection from oxidative-and photooxidative-induced cellular damage and to explore the molecular mechanisms of this cytoprotection.METHODS. Retinal pigment epithelial and retinal photoreceptor cell lines were treated with TP derivatives. Induction of Nrf2 signaling was measured by reporter assay. Cytoprotection was quantified by MTT assay. To determine whether TPs confer in vivo cytoprotection, BALB/c mice were pretreated with CDDO-TFEA, and retinal degeneration was induced by light exposure. To explore the association of TPs with PTEN, a biotinylated derivative of CDDO (CDDO-Bt) was used.RESULTS. Treatment with CDDO-Im-, -TFEA-, or -EA-induced Nrf2 signaling and TP pretreatment protected retinal cell lines from oxidant-induced cell death. The antioxidant and cytoprotective potential of these compounds was then examined in vivo. Treatment of BALB/c mice with CDDO-TFEA induced the Nrf2-regulated transcripts glcl and trx1 in retinal tissue and was protective from photooxidative retinal damage. Treatment with CDDO-Im leads to phosphorylation of AKT. CDDO-Bt directly binds cysteine 124 within PTEN's active site and inhibits PTEN's lipid phosphatase activity in vitro. Thus the stimulation of AKT activity is mediated by TP inhibition of PTEN activity.CONCLUSIONS. These studies highlight the potential of TPs in retinal cytoprotection and implicate PTEN inhibition as a target in cytoprotection. (Invest Ophthalmol Vis Sci. 2009;50:5339-5347) DOI:10.1167/iovs.09-3648