Hypothermia Identifies Dynamin as a Potential Therapeutic Target in Experimental Stroke.
Hypothermia Identifies Dynamin as a Potential Therapeutic Target in Experimental Stroke.
复制标题
DOI：
10.1089/ther.2017.0005
复制
发表时间：
2017-09
影响因子：
1.2
通讯作者：
Jong Youl Kim;Nuri Kim;J. E. Lee;M. Yenari
中科院分区：
文献类型：
--
作者：
Jong Youl Kim;Nuri Kim;J. E. Lee;M. Yenari
细胞凋亡是一种在缺血性脑卒中中被激活的细胞死亡途径。Fas及其配体（FasL）之间的相互作用启动了一个复杂的细胞内事件模式，包括特异性接头蛋白的募集和细胞凋亡的发展。我们最近报道了脑卒中后动力蛋白增加，抑制动力蛋白可改善神经系统预后。动力学蛋白已被证明可以将Fas从内质网转运到细胞表面，在那里它可以与它的配体FasL结合。在许多中风模型中，低温已被证明可以改善预后，这种保护与减少细胞凋亡和Fas表达有关。为了探索动力蛋白对低温神经保护的贡献，我们对小鼠进行了远端大脑中动脉闭塞（dMCAO），并应用了两种冷却模式中的一种：一种是在dMCAO开始时开始冷却（早期低温），另一种是在1小时后开始冷却（延迟低温），与常温（Norm）相比。与常温相比，两种冷却方式均可减少凋亡细胞数量，减少Fas和dynamin的表达。Fas和dynamin在神经元中共表达。神经元培养暴露于缺氧葡萄糖剥夺。低温降低了动力蛋白和Fas的表面表达，这与减少细胞死亡有关。本研究结果提示，动力蛋白可能参与fas介导的凋亡通路，其减少可能与低温神经保护有关。
Apoptosis is a cell death pathway that is activated in ischemic stroke. The interaction between Fas and its ligand (FasL) initiates a complex pattern of intracellular events involving the recruitment of specific adaptor proteins and the development of apoptosis. We recently reported that dynamin is increased after experimental stroke, and its inhibition improves neurological outcome. Dynamin has been shown to transport Fas from the endoplasmic reticulum to the cell surface where it can be bound by its ligand, FasL. Hypothermia has been shown to improve outcome in numerous stroke models, and this protection is associated with reduced apoptosis and Fas expression. To explore the contribution of dynamin to hypothermic neuroprotection, we subjected mice to distal middle cerebral artery occlusion (dMCAO) and applied one of two cooling paradigms: one where cooling began at the onset of dMCAO (early hypothermia) and another where cooling began 1 hour later (delayed hypothermia), compared with normothermia (Norm). Both cooling paradigms reduced numbers of apoptotic cells, as well as Fas and dynamin compared with Norm. Fas and dynamin were co-expressed in neurons. Neuronal cultures were exposed to oxygen glucose deprivation. Hypothermia decreased dynamin as well as surface expression of Fas, and this correlated to reduced cell death. The results of this study suggest that dynamin may participate in the Fas-mediated apoptotic pathway, and its reduction may be linked to hypothermic neuroprotection.