Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain.
Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain.
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组织型纤溶酶原激活剂调节缺血脑中神经元对葡萄糖的摄取
DOI：
10.1523/jneurosci.1241-12.2012
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发表时间：
2012-07-18
期刊：
影响因子：
--
通讯作者：
Yepes M
中科院分区：
文献类型：
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作者：
Wu F;Wu J;Nicholson AD;Echeverry R;Haile WB;Catano M;An J;Lee AK;Duong D;Dammer EB;Seyfried NT;Tong FC;Votaw JR;Medcalf RL;Yepes M
感知和适应缺氧条件的能力在神经元存活中起着关键作用。缺氧诱导大脑皮质神经元释放组织型纤溶酶原激活剂（tPA）。我们发现，释放神经元tPA或重组tPA治疗促进细胞存活在大脑皮层神经元先前暴露于缺氧条件下在体外或实验性脑缺血在体内。我们使用液相色谱和串联质谱的研究表明，tPA激活哺乳动物雷帕霉素靶蛋白（mTOR）通路，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-1 α（HIF-1α）的积累，并诱导和招募HIF-1α调节的葡萄糖GLUT 3神经元转运蛋白到细胞膜。因此，在神经元中过表达tPA的小鼠中使用18-氟脱氧葡萄糖的体内正电子发射断层扫描研究表明，神经元tPA诱导缺血性脑中葡萄糖的摄取，并且这种作用与缺血性病变体积的减少和诱导缺血性卒中后神经学结果的改善相关。我们的数据表明，tPA激活细胞信号通路，使神经元感知和适应氧和葡萄糖剥夺。
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.