Neuroprotective roles of HAX-1 in ischemic neuronal injury
Neuroprotective roles of HAX-1 in ischemic neuronal injury
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DOI：
10.1016/j.expneurol.2021.113642
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发表时间：
2021-02
影响因子：
5.3
通讯作者：
X. Sui;Hideyuki Yoshioka;Yuichiro Fukumoto;K. Kanemaru;H. Kinouchi
中科院分区：
文献类型：
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作者：
X. Sui;Hideyuki Yoshioka;Yuichiro Fukumoto;K. Kanemaru;H. Kinouchi
造血细胞特异性蛋白1相关蛋白X-1（HAX-1）是一种新的线粒体蛋白，可调节氧化应激诱导的细胞凋亡。然而，HAX-1在缺血性神经元损伤中的作用尚未完全阐明。本研究采用在体和离体模型研究了缺血应激后HAX-1的表达及其作用。使用缺乏烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（NOX 2）的基因敲除小鼠检查氧化应激对HAX-1调节的影响，NOX 2是脑缺血后活性氧（ROS）的主要来源。对雄性C57 BL/6 J小鼠进行短暂的前脑缺血，通过阻断双侧颈总动脉22分钟诱导，并分析纹状体样品。在体外缺血实验中，利用大鼠嗜铬细胞瘤细胞系中的氧和葡萄糖剥夺（OGD）。免疫印迹和免疫荧光分析显示，在体和离体缺血后，HAX-1在神经元线粒体中的表达均显著降低。在NOX 2基因敲除小鼠中，与野生型小鼠相比，缺血诱导的HAX-1表达减少和缺血性神经元损伤显著减轻。使用小干扰RNA抑制HAX-1显著增加了OGD后培养细胞的损伤。这些发现表明，HAX-1对缺血性神经元损伤具有神经保护作用，并且通过NOX 2产生的ROS下调HAX-1诱导脑缺血后细胞凋亡。
Hematopoietic cell-specific protein 1 associated protein X-1 (HAX-1) is a novel mitochondrial protein that regulates oxidative stress-induced apoptosis. However, the roles of HAX-1 in ischemic neuronal injury have not been thoroughly elucidated. In this study, the expression and roles of HAX-1 after ischemic stress were investigated usingin vivoandin vitromodels. The effect of oxidative stress on the regulation of HAX-1 was examined using knockout mice lacking nicotinamide-adenine dinucleotide phosphate oxidase 2 (NOX2), which is a major source of reactive oxygen species (ROS) after cerebral ischemia. Male C57BL/6 J mice were subjected to transient forebrain ischemia induced by 22-min occlusion of the bilateral common carotid arteries, and striatum samples were analyzed. Forin vitroischemic experiments, oxygen and glucose deprivation (OGD) in a rat pheochromocytoma cell line was utilized. Western blotting and immunofluorescence analysis revealed HAX-1 expression in neuronal mitochondria, which was significantly decreased after ischemiain vivoandin vitro. In NOX2 knockout mice, ischemia-induced decrease in HAX-1 expression and ischemic neuronal injury was significantly alleviated compared to those in wild-type mice. Inhibition of HAX-1 using small interfering RNA significantly increased injury in cultured cells after OGD. These findings suggest that HAX-1 has a neuroprotective effect against ischemic neuronal injury, and downregulation of HAX-1 by NOX2-produced ROS induces apoptosis after cerebral ischemia.