Inhibition of ROS-induced apoptosis in endothelial cells by nitrone spin traps via induction of phase II enzymes and suppression of mitochondria-dependent pro-apoptotic signaling.
Inhibition of ROS-induced apoptosis in endothelial cells by nitrone spin traps via induction of phase II enzymes and suppression of mitochondria-dependent pro-apoptotic signaling.
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DOI：
10.1016/j.bcp.2012.04.021
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发表时间：
2012-08-15
影响因子：
5.8
通讯作者：
Villamena, Frederick A.
中科院分区：
文献类型：
--
作者：
Das, Amlan;Gopalakrishnan, Bhavani;Voss, Oliver H.;Doseff, Andrea I.;Villamena, Frederick A.
氧化应激是包括炎症、癌症、心血管疾病和神经退行性疾病在内的各种疾病发病的主要病因。由于硝酮类化合物的自旋捕获能力和多种药理作用，其作为治疗剂的应用已引起人们的关注。尽管硝酮的抗氧化性能是众所周知的，但它们调节细胞防御机制对抗氧化应激的机制还没有得到很好的研究，需要进一步阐明。在这里，我们研究了硝酮自旋陷阱对牛主动脉内皮细胞(BAEC)氧化应激的保护作用机制。研究了环硝酮5，5-二甲基吡咯啉N-氧化物(DMPO)和线性硝酮α-苯基N-叔丁基硝酮(PBN)对H_2O_2诱导的细胞毒性的保护作用。PBN或DMPO预先与BAEC孵育可抑制过氧化氢介导的细胞毒性和细胞凋亡。硝酮处理可通过核转位使氧化应激细胞中的核转录因子2(NRF-2)转位，从而诱导和恢复II相抗氧化酶。此外，硝酮类化合物还能抑制H_2O_2诱导的线粒体去极化和caspase-3的激活。在H_2O_2处理前用硝酮预育细胞，可显著下调促凋亡蛋白P53和Bax的表达，上调抗凋亡蛋白Bc l-2和p-Bad的表达。还观察到，NRF-2沉默完全消除了硝酮的保护作用。因此，这些发现表明，硝酮通过调节II相抗氧化酶，从而抑制线粒体依赖的细胞凋亡级联反应，从而保护内皮细胞免受氧化应激的伤害。
Oxidative stress is the main etiological factor behind the pathogenesis of various diseases including inflammation, cancer, cardiovascular and neurodegenerative disorders. Due to the spin trapping abilities and various pharmacological properties of nitrones, their application as therapeutic agent has been gaining attention. Though the antioxidant properties of the nitrones are well known, the mechanisms by which they modulate the cellular defense machinery against oxidative stress is not well investigated and requires further elucidation. Here, we have investigated the mechanisms of cytoprotection of the nitrone spin traps against oxidative stress in bovine aortic endothelial cells (BAEC). Cytoprotective properties of both the cyclic nitrone 5,5-dimethyl-pyrroline N-oxide (DMPO) and linear nitrone alpha-phenyl N-tert-butyl nitrone (PBN) against H2O2-induced cytoxicity were investigated. Preincubation of BAEC with PBN or DMPO resulted in the inhibition of H2O2–mediated cytotoxicity and apoptosis. Nitrone-treatment resulted in the induction and restoration of phase II antioxidant enzymes via nuclear translocation of NF-E2-related factor 2 (Nrf-2) in oxidatively-challenged cells. Furthermore, the nitrones were found to inhibit the mitochondrial depolarization and subsequent activation of caspase-3 induced by H2O2. Significant down-regulation of the pro-apoptotic proteins p53 and Bax, and up-regulation of the anti-apoptotic proteins Bcl-2 and p-Bad were observed when the cells were preincubated with the nitrones prior to H2O2–treatment. It was also observed that Nrf-2 silencing completely abolished the protective effects of nitrones. Hence, these findings suggest that nitrones confer protection to the endothelial cells against oxidative stress by modulating phase II antioxidant enzymes and subsequently inhibiting mitochondria-dependent apoptotic cascade.
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影响因子：
5
作者：
BRADAMANTE, S;MONTI, E;PICCININI, F
通讯作者：
PICCININI, F
影响因子：
4.1
作者：
Balogun, E;Hoque, M;Motterlini, R
通讯作者：
Motterlini, R
影响因子：
4.1
作者：
BOVERIS, A;CHANCE, B
通讯作者：
CHANCE, B
影响因子：
7.3
作者：
Durand, Gregory;Poeggeler, Burkhard;Pucci, Bernard
通讯作者：
Pucci, Bernard
影响因子：
2.9
作者：
Durand, Gregory;Choteau, Fanny;Villamena, Frederick A.
通讯作者：
Villamena, Frederick A.