BACKGROUND Stroke is a leading cause of mortality worldwide. Rac-MAPK kinase 6 (Map2k6) plays important roles in cell proliferation and apoptosis. However, the role played by Map2k6 in stroke injury and the underlying mechanism of action remain unknown. METHODS Mice received cerebral ischemia/reperfusion (I/R) injuries by transient middle cerebral artery occlusion. HT22 cells were subjected to oxygen glucose deprivation and reoxygenation (OGD/R) to simulate an I/R injury. Subsequently, the levels of circ_016719, miR-29c and Map2k6 expression were determined, and their interactions were examined by luciferase assays. Circ_016719 knockdown, miR-29c inhibition or Map2k6 overexpression was induced in HT22 cells; after which, the cells were examined for their viability, apoptosis, autophagy and proliferation, as well their levels of Map2k6, p38, p53, LC3B-I, LC3B-II, Beclin 1, and p62 expression. RESULTS Significantly increased levels of circ_016719 and Map2k6, and decreased levels of miR-29c were observed in both in vivo and in vitro I/R injury models. In HT22 cells, circ_016719 knockdown significantly increased miR-29c expression and cell proliferation, but decreased Map2k6 expression and cell apoptosis. Additionally, significant increases in LC3B-I and p62 levels and decreased LC3B-II levels were observed, indicating that circ_016719 knockdown had significantly inhibited autophagy. Furthermore, additional inhibition of miR-29c markedly suppressed the effects of circ_016719 knockdown; however, that suppression was significantly attenuated by Map2k6 overexpression. Additionally, Map2k6 was identified as a direct target of miR-29c, which in turn, might be sponged by circ_016719. CONCLUSIONS Our results suggest that circ_016719 directly targets miR-29c, and thereby regulates the expression and functions of Map2k6, which significantly contributes to the pro-apoptotic role of circ_016719.

中文翻译：

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Circ_016719通过靶向miR-29c / Map2k6在I / R诱导的神经元细胞凋亡中发挥关键作用。

背景技术中风是世界范围内死亡的主要原因。Rac-MAPK激酶6（Map2k6）在细胞增殖和凋亡中起重要作用。但是，Map2k6在中风损伤中发挥的作用以及潜在的作用机制仍然未知。方法小鼠因短暂性大脑中动脉闭塞而遭受脑缺血/再灌注（I / R）损伤。对HT22细胞进行氧葡萄糖剥夺和复氧（OGD / R）以模拟I / R损伤。随后，确定了circ_016719，miR-29c和Map2k6的表达水平，并通过萤光素酶测定法检查了它们之间的相互作用。在HT22细胞中诱导了circ_016719敲低，miR-29c抑制或Map2k6过表达；之后，检查细胞的活力，凋亡，自噬和增殖以及Map2k6，p38，p53，LC3B-I，LC3B-II，Beclin 1和p62表达。结果在体内和体外I / R损伤模型中均观察到circ_016719和Map2k6的水平显着升高，而miR-29c的水平显着降低。在HT22细胞中，circ_016719敲低显着增加了miR-29c表达和细胞增殖，但降低了Map2k6表达和细胞凋亡。此外，观察到LC3B-I和p62水平显着增加，而LC3B-II水平下降，表明circ_016719敲低显着抑制了自噬。此外，对miR-29c的其他抑制作用显着抑制了circ_016719敲低的效应。但是，该抑制由于Map2k6过表达而大大减弱。此外，将Map2k6鉴定为miR-29c的直接靶标，而circ_016719可能会将其击中。