PHLPP1 gene deletion protects the brain from ischemic injury
PHLPP1 gene deletion protects the brain from ischemic injury
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DOI：
10.1038/jcbfm.2012.150
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发表时间：
2013-02-01
影响因子：
6.3
通讯作者：
Purcell, Nicole H.
中科院分区：
文献类型：
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作者：
Chen, Bo;Van Winkle, Jessica A.;Purcell, Nicole H.
最近发现的蛋白磷酸酶 PHLPP（PH 结构域富含亮氨酸重复蛋白磷酸酶）已被证明可以使 Akt 的疏水基序 (Ser473) 去磷酸化，从而降低 Akt 激酶活性。我们培育了 PHLPP1 敲除 (KO) 小鼠，并用它们来探索增强的体内 Akt 信号传导保护大脑免受缺血性损伤的能力。与野生型 (WT) 小鼠相比，大脑中动脉闭塞 (MCAO) 2 小时的 KO 小鼠大脑显示，再灌注后 Akt 活性显着增加，神经血管损伤减少。值得注意的是，与 WT 相比，PHLPP1 KO 中的梗死体积显着减少（12.7 +/- 2.7% 与 22.9 +/- 3.1%），并且这是通过 Akt 抑制来预防的。来自 KO 小鼠的星形胶质细胞和 PHLPP1 下调的神经元表现出对氧-葡萄糖剥夺的反应增强的 Akt 激活和减少的细胞死亡。因此，PHLPP1 的缺失可以增强神经元和星形胶质细胞中的 Akt 激活，并且可以显着增加 MCAO 后的细胞存活率并缩小梗塞面积。抑制 PHLPP 可能是一种最大程度地减少局灶性缺血后损伤的治疗方法。脑血流与代谢杂志 (2013) 33, 196-204; doi：10.1038/jcbfm.2012.150； 2012 年 10 月 17 日在线发布
A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2 hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7 +/- 2.7% versus 22.9 +/- 3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 196-204; doi:10.1038/jcbfm.2012.150; published online 17 October 2012