Kim Jong Youl, Kim Nuri, Lee Jong Eun, Yenari Midori A
1 Department of Neurology, San Francisco Veterans Affairs Medical Center, University of California , San Francisco, San Francisco, California.
2 Department of Anatomy, Yonsei University College of Medicine , Seoul, Republic of Korea.
Ther Hypothermia Temp Manag. 2017 Sep;7(3):171-177. doi: 10.1089/ther.2017.0005. Epub 2017 Jun 30.
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.
凋亡是一种在缺血性卒中时被激活的细胞死亡途径。Fas与其配体（FasL）之间的相互作用引发了一系列复杂的细胞内事件，包括特定衔接蛋白的募集和凋亡的发生。我们最近报道，实验性卒中后发动蛋白增加，抑制其表达可改善神经功能结局。已表明发动蛋白可将Fas从内质网转运至细胞表面，在那里它可与配体FasL结合。在众多卒中模型中，低温已被证明可改善结局，这种保护作用与凋亡减少和Fas表达降低有关。为了探究发动蛋白在低温神经保护中的作用，我们将小鼠进行大脑中动脉远端闭塞（dMCAO），并应用两种降温模式之一：一种是在dMCAO开始时即开始降温（早期低温），另一种是在1小时后开始降温（延迟低温），并与正常体温（Norm）组进行比较。与Norm组相比，两种降温模式均减少了凋亡细胞的数量，以及Fas和发动蛋白的表达。Fas和发动蛋白在神经元中共表达。将神经元培养物暴露于氧糖剥夺环境中。低温降低了发动蛋白以及Fas的表面表达，这与细胞死亡减少相关。本研究结果提示，发动蛋白可能参与Fas介导的凋亡途径，其表达降低可能与低温神经保护作用有关。
