Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size
Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size
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DOI：
10.1038/jcbfm.2013.68
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发表时间：
2013-08-01
影响因子：
6.3
通讯作者：
Sen, Chandan K.
中科院分区：
文献类型：
--
作者：
Khanna, Savita;Rink, Cameron;Sen, Chandan K.
已知谷氨酸耗竭和花生四烯酸的12-脂氧合酶依赖性代谢与急性缺血性卒中相关的神经变性有关。本研究的目的是探讨miR-29在急性缺血性卒中相关神经退行性变中的意义。花生四烯酸损伤谷胱甘肽缺陷细胞引起的神经细胞死亡之前，12-脂氧合酶依赖的损失的miR-29 b。递送miR-29 b模拟物以钝化这种损失是神经保护性的。miR-29 b抑制增强了这种神经细胞死亡。12-脂氧合酶敲除和抑制剂减弱了攻击细胞中miR-29 b的丢失。在体内，由大脑中动脉闭塞引起的中风之后是更高的12-脂氧合酶活性和miR-29 b的损失，如在激光捕获的梗死部位组织中检测到的。12-脂氧合酶敲除小鼠表现出对这种miR损失的保护。miR-29 b基因递送显著减弱了卒中诱导的脑损伤。口服补充维生素E 12-脂氧合酶抑制剂α-生育三烯酚，挽救了卒中诱导的miR-29 b丢失并使病变大小最小化。这项工作提供了第一个证据，证明梗死部位miR-29 b的丢失是卒中病变的关键因素。这种损失是由12-脂氧合酶途径的活性贡献的，提供了将花生四烯酸代谢与中风中的miR依赖性机制联系起来的首次证据。
Glutathione depletion and 12-lipoxygenase-dependent metabolism of arachidonic acid are known to be implicated in neurodegeneration associated with acute ischemic stroke. The objective of this study was to investigate the significance of miR-29 in neurodegeneration associated with acute ischemic stroke. Neural cell death caused by arachidonic acid insult of glutathione-deficient cells was preceded by a 12-lipoxygenase-dependent loss of miR-29b. Delivery of miR-29b mimic to blunt such loss was neuroprotective. miR-29b inhibition potentiated such neural cell death. 12-Lipoxygenase knockdown and inhibitors attenuated the loss of miR-29b in challenged cells. In vivo, stroke caused by middle-cerebral artery occlusion was followed by higher 12-lipoxygenase activity and loss of miR-29b as detected in laser-captured infarct site tissue. 12-Lipoxygenase knockout mice demonstrated protection against such miR loss. miR-29b gene delivery markedly attenuated stroke-induced brain lesion. Oral supplementation of a-tocotrienol, a vitamin E 12-lipoxygenase inhibitor, rescued stroke-induced loss of miR-29b and minimized lesion size. This work provides the first evidence demonstrating that loss of miR-29b at the infarct site is a key contributor to stroke lesion. Such loss is contributed by activity of the 12-lipoxygenase pathway providing maiden evidence linking arachidonic acid metabolism to miR-dependent mechanisms in stroke.