Protection of neuroblastoma Neuro2A cells from hypoxia-induced apoptosis by cyclic phosphatidic acid (cPA).
Protection of neuroblastoma Neuro2A cells from hypoxia-induced apoptosis by cyclic phosphatidic acid (cPA).
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DOI：
10.1371/journal.pone.0051093
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Murakami-Murofushi K
中科院分区：
文献类型：
--
作者：
Gotoh M;Sano-Maeda K;Murofushi H;Murakami-Murofushi K
环状磷脂酸 (cPA) 是一种天然存在的磷脂介体，在其甘油主链的 sn-2 和 sn-3 位置上具有独特的环状磷酸环。我们之前已经证明，cPA 显着抑制缺血引起的迟发性神经元死亡和大鼠海马 CA1 区神经胶质原纤维酸性蛋白的积累。这些结果表明，全身给予cPA可以保护海马神经元免受缺血诱导的延迟性神经元细胞死亡。在目前的研究中，我们研究了cPA对体外缺氧引起的神经细胞死亡的影响以及这些影响背后的分子机制。我们使用氯化钴 (CoCl2) 将细胞暴露在体外缺氧条件下。用 CoCl2 处理小鼠神经母细胞瘤 (Neuro2A) 细胞可诱导核 DNA 浓缩和磷脂酰丝氨酸暴露。然而，添加cPA会以cPA剂量依赖性方式抑制CoCl2诱导的细胞凋亡，并减弱CoCl2引起的Bax/Bcl-2比值的增加。定量PCR分析表明，Neuro2A细胞强烈表达LPA1、LPA2和LPA6，它们是可被cPA激活的G蛋白偶联受体。迄今为止，LPA1 和 LPA2 据报道具有抗凋亡活性。因此，为了评估LPA1和LPA2对cPA诱导的神经保护功能的作用，采用选择性LPA1和LPA3拮抗剂Ki16425来了解LPA1的功能，并使用siRNA来敲低LPA2的表达。根据我们的结果，我们提出 cPA 诱导的 Neuro2A 细胞免受 CoCl2 诱导的缺氧损伤的保护是通过 LPA2 介导的。
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We have previously shown that cPA significantly suppresses ischemia-induced delayed neuronal death and the accumulation of glial fibrillary acidic protein in the CA1 region of the rat hippocampus. These results indicated that the systemic administration of cPA can protect hippocampal neurons against ischemia-induced delayed neuronal cell death. In the current study, we investigated the effects of cPA on neuronal cell death caused by hypoxia in vitro and the molecular mechanisms underlying these effects. We used cobalt chloride (CoCl2) to expose cells to hypoxic conditions in vitro. Treating mouse neuroblastoma (Neuro2A) cells with CoCl2 induced nuclear DNA condensation and phosphatidylserine exposure. However, adding cPA led to the suppression of CoCl2-induced apoptosis in a cPA dose-dependent manner and attenuated the increase in the Bax/Bcl-2 ratio caused by CoCl2. Quantitative PCR analysis showed that Neuro2A cells strongly express the LPA1, LPA2, and LPA6, which are G-protein coupled receptors that can be activated by cPA. To date, LPA1 and LPA2 have been reported to exhibit antiapoptotic activity. Therefore, to assess the roles of LPA1 and LPA2 on cPA-induced neuroprotective functions, Ki16425, a selective LPA1 and LPA3 antagonist, was adopted to know the LPA1 function and siRNA was used to knockdown the expression of LPA2. On the basis of our results, we propose that cPA-induced protection of Neuro2A cells from CoCl2-induced hypoxia damage is mediated via LPA2.
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