Department of Critical Care Medicine, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen 518020, PR China.
Department of Neurology, Shijiazhuang Huayao Hospital of North China Medical and Health Group, Shijiazhuang 050000, PR China.
Exp Neurol. 2023 Jan;359:114270. doi: 10.1016/j.expneurol.2022.114270. Epub 2022 Nov 5.
Early brain injury (EBI) refers to early-onset secondary complications that occur after subarachnoid hemorrhage (SAH), and associated with high rate of disability and mortality. Recent investigations have indicated microRNA-26b (miR-26b) as a biomarker in the progression of SAH. Accordingly, the present study was designed to elucidate the role of miR-26b in influencing EBI following SAH and the downstream mechanisms.
Firstly, SAH rat models and neuron injury models were developed to assess the effect of miR-26b on EBI-like symptoms and subsequent inflammation. Dual-luciferase reporter gene assay was further implemented to evaluate the binding of miR-26b to its putative target gene STAT3. Loss-of-function and rescue experiments were performed to assess the functionality of miR-26b-mediated STAT3 in both models.
miR-26b was found to target KLF4 and negative-modulate its expression, whereby aggravating EBI and inflammatory response in SAH rat models and stimulating hemoglobin-induced apoptosis in astrocytes. On the other hand, silencing of miR-26b reversed these changes in SAH rat models and hemoglobin (Hb)-induced astrocytes. miR-26b could further activate STAT3 via down-regulation of KLF4. Furthermore, KLF4 knockdown up-regulated HMGB1 to aggravate EBI following SAH.
Collectively, our findings highlighted the ameliorative effect of miR-26b inhibition on EBI in SAH and the possible mechanism associated with the KLF4/STAT3/HMGB1 axis.
早期脑损伤（EBI）是指蛛网膜下腔出血（SAH）后早期发生的继发性并发症，与高残疾率和高死亡率相关。最近的研究表明 microRNA-26b（miR-26b）是 SAH 进展中的一个生物标志物。因此，本研究旨在阐明 miR-26b 在影响 SAH 后 EBI 中的作用及其下游机制。
首先，建立了 SAH 大鼠模型和神经元损伤模型，以评估 miR-26b 对 EBI 样症状及随后炎症的影响。进一步进行双荧光素酶报告基因检测，以评估 miR-26b 与其假定靶基因 STAT3 的结合。进行基因敲低和挽救实验，以评估 miR-26b 介导的 STAT3 在两种模型中的功能。
miR-26b 被发现可靶向 KLF4 并负调控其表达，从而加重 SAH 大鼠模型中的 EBI 和炎症反应，并刺激星形胶质细胞中血红蛋白诱导的细胞凋亡。另一方面，沉默 miR-26b 可逆转 SAH 大鼠模型和血红蛋白（Hb）诱导的星形胶质细胞中的这些变化。miR-26b 可通过下调 KLF4 进一步激活 STAT3。此外，KLF4 敲低可上调 HMGB1，从而加重 SAH 后的 EBI。
总之，我们的研究结果强调了 miR-26b 抑制对 SAH 中 EBI 的改善作用及其与 KLF4/STAT3/HMGB1 轴相关的可能机制。
