Multiple factors are known to contribute to the pathogenesis of cerebral ischemic injury, including microRNAs (miRNAs). However, the precise mechanism of miRNAs involvement in cerebral ischemia remains largely unclear. In the current study, we found that miR-217 was significantly upregulated in ischemic stroke models, and the upregulation of miR-217 was associated with the development of post-stroke cognitive impairment. Further investigation revealed that myocyte enhancer factor 2D (MEF2D) was the direct target of miR-217. In vitro experiments showed that miR-217 promoted aggregation of histone deacetylase 5 (HDAC5) in cell nuclei by targeting MEF2D, which led to decreased expression of interleukin (IL)-10. In addition, miR-217 inhibited the expression of NADH dehydrogenase subunit 6 (ND6) in a MEF2D-dependent manner. Overexpression of MEF2D can reverse oxygen-glucose deprivation (OGD)-induced downregulation of ND6 and OGD-mediated neuronal apoptosis, and also reduce the elevated generation of reactive oxygen species (ROS) induced by OGD. Additionally, we found that in vivo administration of MEF2D overexpression plasmids increased IL-10 production and ameliorated cognitive impairment after cerebral ischemia. Taken together, these findings reveal a novel pathogenetic mechganism of cerebral ischemia-related brain injury involving the miR-217/MEF2D/HDAC5 axis and the miR-217/MEF2D/ND6 axis.

中文翻译：

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miR-217调控的MEF2D-HDAC5/ND6信号通路参与脑缺血后氧化应激和炎症反应。

已知多种因素有助于脑缺血性损伤的发病机制，包括微 RNA (miRNA)。然而，miRNAs 参与脑缺血的确切机制仍不清楚。在目前的研究中，我们发现 miR-217 在缺血性卒中模型中显着上调，并且 miR-217 的上调与卒中后认知障碍的发展有关。进一步的研究表明，心肌细胞增强因子 2D (MEF2D) 是 miR-217 的直接靶点。体外实验表明，miR-217 通过靶向 MEF2D 促进组蛋白脱乙酰酶 5 (HDAC5) 在细胞核中的聚集，从而导致白细胞介素 (IL)-10 的表达降低。此外，miR-217 以 MEF2D 依赖性方式抑制 NADH 脱氢酶亚基 6 (ND6) 的表达。MEF2D 的过表达可以逆转氧葡萄糖剥夺 (OGD) 诱导的 ND6 下调和 OGD 介导的神经元凋亡，还可以减少 OGD 诱导的活性氧 (ROS) 产生的增加。此外，我们发现 MEF2D 过表达质粒的体内给药增加了 IL-10 的产生并改善了脑缺血后的认知障碍。总之，这些发现揭示了一种新的脑缺血相关脑损伤的发病机制，涉及 miR-217/MEF2D/HDAC5 轴和 miR-217/MEF2D/ND6 轴。我们发现 MEF2D 过表达质粒的体内给药增加了 IL-10 的产生并改善了脑缺血后的认知障碍。总之，这些发现揭示了一种新的脑缺血相关脑损伤的发病机制，涉及 miR-217/MEF2D/HDAC5 轴和 miR-217/MEF2D/ND6 轴。我们发现 MEF2D 过表达质粒的体内给药增加了 IL-10 的产生并改善了脑缺血后的认知障碍。总之，这些发现揭示了一种新的脑缺血相关脑损伤的发病机制，涉及 miR-217/MEF2D/HDAC5 轴和 miR-217/MEF2D/ND6 轴。