Anesthesiology Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Radiotherapy Department, Shaanxi Provincial Tumor Hospital, Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, China.
Clin Exp Pharmacol Physiol. 2020 Jun;47(6):1020-1029. doi: 10.1111/1440-1681.13265. Epub 2020 Feb 10.
MicroRNAs (miRNAs) have emerged as critical regulators of neuronal survival during cerebral ischaemia/reperfusion injury. Accumulating evidence has shown that miR-199a-5p plays a crucial role in regulating apoptosis and survival in various cell types. However, whether miR-199a is involved in regulating neuronal survival during cerebral ischaemia/reperfusion injury remains unknown. In this study, we aimed to explore the biological role of miR-199a-5p in regulating neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R), an in vitro cellular model of cerebral ischaemia and reperfusion injury. We found that miR-199a-5p expression was significantly altered in neurons in response to OGD/R treatment. Overexpression of miR-199a-5p facilitated OGD/R-induced apoptosis and reactive oxygen species (ROS) production, whereas miR-199a-5p inhibition alleviated OGD/R-induced apoptosis and ROS production. Notably, our results identified Brahma-related gene 1 (Brg1) as a target gene of miR-199a-5p. Moreover, inhibition of miR-199a-5p promoted the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signalling via targeting Brg1. However, silencing of Brg1 markedly reversed the miR-199a-5p inhibition-mediated neuroprotective effect. Taken together, our results suggest that downregulation of miR-199a-5p protects neurons from OGD/R-induced neuronal injury through upregulating Brg1 to activate Nrf2/HO-1 signalling. The miR-199a-5p/Brg1/Nrf2/HO-1 regulation axis may play an important role in regulating neuronal survival during cerebral ischaemic/reperfusion injury in vivo.
微小 RNA（miRNAs）已成为脑缺血/再灌注损伤期间神经元存活的关键调节因子。越来越多的证据表明，miR-199a-5p 在调节各种细胞类型中的细胞凋亡和存活中发挥着关键作用。然而，miR-199a 是否参与调节脑缺血/再灌注损伤期间的神经元存活仍不清楚。在这项研究中，我们旨在探讨 miR-199a-5p 在调节氧葡萄糖剥夺/复氧（OGD/R）诱导的神经元损伤中的生物学作用，OGD/R 是脑缺血和再灌注损伤的体外细胞模型。我们发现，神经元对 OGD/R 处理的反应中 miR-199a-5p 的表达明显改变。miR-199a-5p 的过表达促进了 OGD/R 诱导的细胞凋亡和活性氧（ROS）的产生，而 miR-199a-5p 的抑制减轻了 OGD/R 诱导的细胞凋亡和 ROS 的产生。值得注意的是，我们的结果确定了 Brg1 是 miR-199a-5p 的靶基因。此外，通过靶向 Brg1，抑制 miR-199a-5p 促进了核因子-红细胞 2 相关因子 2（Nrf2）/血红素加氧酶-1（HO-1）信号的激活。然而，沉默 Brg1 显著逆转了 miR-199a-5p 抑制介导的神经保护作用。总之，我们的结果表明，下调 miR-199a-5p 通过上调 Brg1 来激活 Nrf2/HO-1 信号，从而保护神经元免受 OGD/R 诱导的神经元损伤。miR-199a-5p/Brg1/Nrf2/HO-1 调节轴可能在调节体内脑缺血/再灌注损伤期间的神经元存活中发挥重要作用。
