Department of Neurology, The People's Hospital of Kaizhou District, Chongqing 405400, China.
Department of Nephrology, The People's Hospital of Kaizhou District, Chongqing 405400, China.
J Stroke Cerebrovasc Dis. 2022 Jul;31(7):106443. doi: 10.1016/j.jstrokecerebrovasdis.2022.106443. Epub 2022 Apr 26.
Intracerebral hemorrhage (ICH) is the most devastating stroke subtype. Transcription factor Forkhead box O1 (FoxO1) is extensively implicated in cerebral injury. This study investigated the mechanism of FoxO1 in neurological function recovery in ICH mice.
A murine model of ICH was established. The modified neurological severity score (mNSS), forelimb placement test, and corner turn test were adopted to evaluate the neurological function of mice. The brain water content was measured and the pathological changes of cerebral tissues were observed. The levels of IL-1β, IL-6, and TNF-α were determined. The expressions of FoxO1, lncRNA GAS5, miR-378a-5p, and heat shock 70 kDa protein 5 (Hspa5) in mouse cerebral tissues were examined. The binding relationships among FoxO1, lncRNA GAS5, miR-378a-5p, and Hspa5 were validated. Functional rescue experiments were designed to verify the role of lncRNA GAS5/miR-378a-5p/Hspa5 axis in neurological function recovery in ICH mice.
FoxO1 was highly expressed in cerebral tissues of ICH mice. FoxO1 silencing facilitated neurological function recovery in ICH mice, evidenced by decreased mNSS, improved forelimb placement rate, reduced turning defects, declined brain water content, relieved edema, intracellular vacuoles, and inflammatory cell infiltration, and reduced IL-1β, IL-6, and TNF-α levels. FoxO1 enhanced lncRNA GAS5 expression by binding to its promoter. LncRNA GAS5 facilitated Hspa5 transcription by sponging miR-378a-5p. Intervention of lncRNA GAS5/miR-378a-5p/Hspa5 axis reversed the promoting effect of FoxO1 silencing on the neurological function recovery in ICH mice.
FoxO1 silencing facilitated neurological function recovery in ICH mice via the lncRNA GAS5/miR-378a-5p/Hspa5 axis.
脑出血（ICH）是最具破坏性的中风类型。转录因子叉头框 O1（FoxO1）广泛参与脑损伤。本研究探讨了 FoxO1 在 ICH 小鼠神经功能恢复中的机制。
建立了小鼠 ICH 模型。采用改良神经严重程度评分（mNSS）、前肢放置试验和转角试验评估小鼠神经功能。测量脑水含量，观察脑组织病理变化。测定白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平。检测小鼠脑组织中 FoxO1、长链非编码 RNA GAS5、miR-378a-5p 和热休克 70kDa 蛋白 5（Hspa5）的表达。验证 FoxO1、长链非编码 RNA GAS5、miR-378a-5p 和 Hspa5 之间的结合关系。设计功能恢复实验验证 lncRNA GAS5/miR-378a-5p/Hspa5 轴在 ICH 小鼠神经功能恢复中的作用。
FoxO1 在 ICH 小鼠脑组织中高表达。FoxO1 沉默促进 ICH 小鼠神经功能恢复，表现为 mNSS 降低，前肢放置率提高，转角缺陷减少，脑水含量降低，水肿、细胞内空泡和炎性细胞浸润减轻，IL-1β、IL-6 和 TNF-α水平降低。FoxO1 通过与启动子结合增强 lncRNA GAS5 的表达。lncRNA GAS5 通过海绵 miR-378a-5p 促进 Hspa5 转录。干预 lncRNA GAS5/miR-378a-5p/Hspa5 轴逆转了 FoxO1 沉默对 ICH 小鼠神经功能恢复的促进作用。
FoxO1 沉默通过 lncRNA GAS5/miR-378a-5p/Hspa5 轴促进 ICH 小鼠神经功能恢复。
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