Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China.
Department of Anesthesiology, Linzhi People's Hospital, Linzhi, Tibet, China.
Oxid Med Cell Longev. 2020 Oct 5;2020:6454281. doi: 10.1155/2020/6454281. eCollection 2020.
Cerebral ischemic stroke is a refractory disease which seriously endangers human health. Remote ischemic perconditioning (RiPerC) by which the sublethal ischemic stimulus is administered during the ischemic event is beneficial after an acute stroke. However, the regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear.
In the present study, we investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). Forty-eight adult male Sprague-Dawley (SD) rats were injected intracerebroventricularly with miR-98 agomir, miR-98 antagomir, or their negative controls (agomir-NC, antagomir-NC) 2 h before MCAO or MCAO+RiPerC followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. The expression of miR-98, PIK3IP1, and tight junction proteins in rat hippocampus and cerebral cortex tissues was detected by quantitative polymerase chain reaction (qPCR) and Western blot (WB). Enzyme-linked immunosorbent assay (ELISA) was used to assess the IL-1, IL-6, and TNF- levels in the rat serum.
The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Then, we found that PIK3IP1 was a potential target of miR-98. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. But treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled.
Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, thus reducing the cerebral ischemia-reperfusion injury.
脑缺血性中风是一种严重危害人类健康的难治性疾病。在急性中风后，给予亚致死性缺血刺激的远程缺血预处理（RiPerC）是有益的。然而，减轻脑缺血损伤的 RiPerC 的调节机制尚不完全清楚。
在本研究中，我们在大脑中动脉闭塞（MCAO）诱导的大鼠缺血模型中研究了 RiPerC 的调节机制。48 只成年雄性 Sprague-Dawley（SD）大鼠在 MCAO 前 2 小时经侧脑室注射 miR-98 agomir、miR-98 antagomir 或其阴性对照物（agomir-NC、antagomir-NC），然后进行动物行为测试和 MCAO 后 24 小时的梗死体积测量。通过定量聚合酶链反应（qPCR）和 Western blot（WB）检测大鼠海马和皮质组织中 miR-98、PIK3IP1 和紧密连接蛋白的表达。酶联免疫吸附试验（ELISA）用于评估大鼠血清中 IL-1、IL-6 和 TNF-α 的水平。
结果表明，在 MCAO 组中，PIK3IP1 的表达上调，但 RiPerC 处理后表达降低。然后，我们发现 PIK3IP1 是 miR-98 的潜在靶标。与对照组大鼠相比，miR-98 agomir 治疗可减少梗死体积、减轻脑水肿并改善神经功能。但在 RiPerC 组中用 miR-98 antagomir 治疗，对脑缺血损伤的保护作用被取消。
我们的发现表明，RiPerC 通过上调 miR-98 抑制 MCAO 诱导的 PIK3IP1 表达，从而通过 PI3K/AKT 信号通路减少 PIK3IP1 诱导的细胞凋亡，从而减轻脑缺血再灌注损伤。
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