Upregulation of MicroRNA-128 in the Peripheral Blood of Acute Ischemic Stroke Patients is Correlated with Stroke Severity Partially through Inhibition of Neuronal Cell Cycle Reentry
Upregulation of MicroRNA-128 in the Peripheral Blood of Acute Ischemic Stroke Patients is Correlated with Stroke Severity Partially through Inhibition of Neuronal Cell Cycle Reentry
复制标题
急性缺血性中风患者外周血中 MicroRNA-128 的上调与中风严重程度相关，部分是通过抑制神经元细胞周期折返。
DOI：
10.1177/0963689719846848
复制
发表时间：
2019-07-01
影响因子：
3.3
通讯作者：
Luo, Yumin
中科院分区：
文献类型：
--
作者：
Liu, Ping;Han, Ziping;Luo, Yumin
MIR-128是人脑中含量最丰富的miRNAs之一，已有报道通过抑制P38αMAPK来保护MCAO小鼠。它是否参与了急性缺血性卒中患者的发病机制还有待确定。本研究的重点是miR-128的临床重要性及其潜在机制。我们用RT-PCR检测了急性缺血性中风患者循环淋巴细胞、中性粒细胞和血浆中miR-128的水平。急性缺血性卒中患者循环淋巴细胞、中性粒细胞和血浆中MIR-128水平显著升高。此外，循环淋巴细胞miR-128水平与脑梗塞体积、发病后7天的NIHSS评分和发病90天的MRS呈正相关。随后的KEGG通路分析表明，MAPK信号通路和细胞周期是miR-128靶向的通路之一。MCAO小鼠血浆miR-128水平与周围炎性细胞数无相关性，但在同侧脑组织中，miR-128在半影区减少，而在梗死灶中心增加。此外，体外研究表明miR-128 Anagomir加重了OGD/R刺激诱导的原代神经元损伤和细胞周期再激活，其机制可能与增加细胞周期蛋白A2、PTEN和ERK的表达以及促进PTEN和ERK的磷酸化有关。以上结果提示，急性缺血性卒中患者外周血淋巴细胞miR-128表达上调与卒中严重程度有关，miR-128拮抗剂通过促进神经元细胞周期重入而加重缺血再灌注所致的神经元损伤。
MiR-128, one of the most enriched miRNAs in the human brain, has been reported to protect MCAO mice via inhibiting P38 alpha MAPK. Whether it is involved in pathogenesis in acute ischemic stroke patients remains to be determined. The present study focused on the clinical importance of miR-128 and its underlying mechanisms. We detected miR-128 levels in the circulating lymphocytes, neutrophils, and plasma of acute ischemic stroke patients by using RT-PCR. miR-128 levels were significantly elevated in circulating lymphocytes, neutrophils, and plasma of patients with acute ischemic stroke. In addition, miR-128 levels in circulating lymphocytes correlated positively with the infarction volume, NIHSS scores at 7 days and mRS at 90 days after ischemic stroke onset. Subsequent KEGG pathway analysis showed that the MAPK signaling pathway and cell cycle are among the pathways targeted by miR-128. Although no correlation was found between miR-128 in plasma and peripheral inflammatory cell numbers, miR-128 decreased in the penumbra and increased in the infarction core of ipsilateral brain tissues in MCAO mice. Moreover, an in vitro study demonstrated that miR-128 antagomir aggravated primary neuronal damage and exacerbated cell cycle reactivation induced by OGD/R stimulation; the underlying mechanism involved increasing cyclin A2, PTEN, and ERK expression and promoting phosphorylation of PTEN and ERK. From the above results, we concluded that the upregulation of miR-128 in circulating lymphocytes of acute ischemic stroke patients was correlated with stroke severity and miR-128 antagomir exacerbated ischemia-reperfusion induced neuronal injury via promoting neuronal cell cycle reentry.