15-Deoxy-Δ12,14-prostaglandin J2 rescues PC12 cells from H2O2-induced apoptosis through Nrf2-mediated upregulation of heme oxygenase-1: Potential roles of Akt and ERK1/2
15-Deoxy-Δ12,14-prostaglandin J2 rescues PC12 cells from H2O2-induced apoptosis through Nrf2-mediated upregulation of heme oxygenase-1: Potential roles of Akt and ERK1/2
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DOI：
10.1016/j.bcp.2008.08.007
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发表时间：
2008-12-01
影响因子：
5.8
通讯作者：
Surh, Young-Joon
中科院分区：
文献类型：
--
作者：
Kim, Ji-Woo;Li, Mei-Hua;Surh, Young-Joon
由活性氧中间体引起的氧化应激与多种人类疾病有关，包括类风湿性关节炎和神经退行性疾病。 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) 是前列腺素 D-2 的末端脱水产物，是过氧化物酶体增殖物激活受体 γ 的内源性配体，具有多种生物活性，包括促凋亡活性。最近的研究表明，这种环戊烯酮前列腺素在无毒浓度下也可以发挥抗凋亡或细胞保护作用。在本研究中，使用培养的大鼠嗜铬细胞瘤(PC12) 细胞探讨了15d-PGJ(2) 对H2O2 诱导的细胞毒性的保护作用的潜在机制。用 H2O2 处理的 PC12 细胞发生细胞凋亡，用无毒浓度的 15d-PGJ(2) 预处理可减弱细胞凋亡。用 15d-PGJ(2) 处理 PC12 细胞会导致核转位、DNA 结合和 NF-E2 相关因子 2 (Nrf2) 转录活性增加，导致血红素加氧酶-1 (HO-1) 表达上调，从而提供针对 H2O2 衍生的氧化细胞毒性的适应性生存反应。用显性失活 Nrf2 基因转染 PC12 细胞消除了 15d-PGJ(2) 衍生的 HO-1 表达诱导。此外，显性失活突变以及 Akt/蛋白激酶 B 或细胞外信号调节激酶 1/2 (ERK1/2) 的药理学抑制可抑制 15d-PGJ(2) 介导的 Nrf2-ARE 结合和 ARE 荧光素酶活性的增加。总而言之，这些发现表明 15d-PGJ(2) 通过激活 Akt 和 ERK 信号通路增强细胞抗氧化防御能力，从而导致 Nrf2 激活，并随后诱导 HO-1，从而保护 PC12 细胞免受 H2O2 诱导的氧化细胞死亡。 (c) 2008 年，爱思唯尔公司出版。
Oxidative stress induced by reactive oxygen intermediates has been implicated in a variety of human diseases including rheumatoid arthritis and neuro degenerative disorders. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a terminal dehydration product of prostaglandin D-2, is an endogenous ligand of peroxisome proliferator-activated receptor-gamma and exhibits a number of biological activities including the proapoptotic activity. Recent studies have revealed that this cyclopentenone prostaglandin, at non-toxic concentrations, can also exert antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of 15d-PGJ(2) on the H2O2-induced cytotoxicty were explored using cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with H2O2 underwent apoptosis, which was attenuated by pretreatment with non-toxic concentrations of 15d-PGJ(2). Treatment of the PC12 cells with 15d-PGJ(2) resulted in increased nuclear translocation, DNA-binding and transcriptional activity of NF-E2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase-1 (HO-1) expression, which provided an adaptive survival response against the H2O2-derived oxidative cytotoxicity. Transfection of PC12 cells with dominant-negative Nrf2 gene abolished the 15d-PGJ(2)-derived induction of HO-1 expression. Moreover, the 15d-PGJ(2)-mediated increases in Nrf2-ARE binding and ARE luciferase activity were suppressed by the dominant-negative mutation as well as the pharmacological inhibition of Akt/protein kinase B or extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these findings suggest that 15d-PGJ(2) augments cellular antioxidant defense capacity through activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction, thereby protecting the PC12 cells from H2O2-induced oxidative cell death. (c) 2008 Published by Elsevier Inc.