Dong Zhiping, Liang Xiaoshan, Zhang Qiang, Luo Suhui, Liu Huan, Wang Xuan, Sai Na, Zhang Xumei
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, 300134, China.
Transl Stroke Res. 2021 Oct;12(5):829-843. doi: 10.1007/s12975-020-00860-7. Epub 2020 Oct 10.
Ischemic stroke remains one of the most common causes of death and disability worldwide. The stroke patients with an inadequate intake of folic acid tend to have increased brain injury and poorer prognosis. However, the precise mechanisms underlying the harmful effects of folic acid deficiency (FD) in ischemic stroke is still elusive. Here, we aimed to test the hypothesis that mitochondrial localized STAT3 (mitoSTAT3) expression may be involved in the process of neuronal damage induced by FD in in vivo and in vitro models of ischemic stroke. Our results exhibited that FD increased infarct size and aggravated the damage of mitochondrial ultrastructure in ischemic brains. Meanwhile, FD upregulated the phosphorylation levels of mitoSTAT3 at Tyr705 (Y705) and Ser727 (S727) sites in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and oxygen-glucose deprivation followed by reperfusion (OGD/R) N2a cells. Furthermore, the inhibition of JAK2 by AG490 led to a significant decrease in FD-induced phosphorylation of Y705, while S727 phosphorylation was unaffected. Conversely, U0126 and LY294002, which respectively inhibited phosphorylation of ERK1/2 and Akt, partially prevented S727 phosphorylation, but had limited effects on the level of pY705, suggesting that phosphorylation of Y705 and S727 is regulated via independent mechanisms in FD-treated brains.
缺血性中风仍然是全球范围内最常见的死亡和残疾原因之一。叶酸摄入不足的中风患者往往脑损伤加重，预后较差。然而，叶酸缺乏（FD）在缺血性中风中产生有害影响的具体机制仍不清楚。在此，我们旨在验证线粒体定位的信号转导和转录激活因子3（mitoSTAT3）表达可能参与FD在缺血性中风体内和体外模型中诱导神经元损伤过程的假说。我们的结果显示，FD增加了缺血性脑梗死体积，加重了线粒体超微结构损伤。同时，在大鼠大脑中动脉闭塞/再灌注（MCAO/R）模型及氧糖剥夺复氧（OGD/R）的N2a细胞中，FD上调了mitoSTAT3在Tyr705（Y705）和Ser727（S727）位点的磷酸化水平。此外，AG490抑制JAK2导致FD诱导的Y705磷酸化显著降低，而S727磷酸化不受影响。相反，分别抑制ERK1/2和Akt磷酸化的U0126和LY294002部分阻止了S727磷酸化，但对pY705水平影响有限，这表明在FD处理的大脑中，Y705和S727的磷酸化是通过独立机制调控的。
