Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci. 2012 Jul 18;32(29):9848-58. doi: 10.1523/JNEUROSCI.1241-12.2012.
The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway, which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with a decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.
感知和适应缺氧环境的能力在神经元存活中起着关键作用。缺氧诱导脑皮质神经元释放组织型纤溶酶原激活物（tPA）。我们发现，神经元 tPA 的释放或用重组 tPA 处理可促进体外先前暴露于缺氧条件或体内实验性脑缺血的脑皮质神经元的细胞存活。我们使用液相色谱和串联质谱的研究表明，tPA 激活了雷帕霉素靶蛋白（mTOR）途径，该途径使细胞过程适应能量和代谢资源的可用性。我们发现 mTOR 激活导致缺氧诱导因子-1α（HIF-1α）的积累，并诱导和募集到 HIF-1α 调节的神经元葡萄糖转运蛋白 GLUT3 的细胞膜上。因此，在过表达神经元 tPA 的小鼠的体内正电子发射断层扫描研究中，用 18-氟脱氧葡萄糖进行示踪，结果显示神经元 tPA 诱导缺血脑内葡萄糖摄取，并且这种作用与缺血性损伤体积减小以及诱导缺血性中风后神经功能结局改善相关。我们的数据表明，tPA 激活了一种细胞信号通路，使神经元能够感知和适应缺氧和葡萄糖剥夺。
