MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral ischemia
MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral ischemia
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MicroRNA-182 通过下调脑缺血中的 mTOR/FOXO1 通路加剧血脑屏障 (BBB) 破坏
DOI：
10.1096/fj.201903092r
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Wang Guangyou
中科院分区：
文献类型：
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作者：
Zhang Tongshuai;Tian Chao;Wu Jinrong;Zhang Yao;Wang Jinghua;Kong Qingfei;Mu Lili;Sun Bo;Ai Tianhong;Wang Yue;Zhao Wei;Wang D;an;Li Hulun;Wang Guangyou
脑缺血会导致血脑屏障（BBB）的结构和功能受损，减轻BBB的破坏对于缺血性中风的治疗和预后具有重要意义。最近，microRNA已被证明在BBB完整性中发挥关键作用。然而，microRNA-182（miR-182）在缺血性卒中中影响BBB的潜在机制仍不清楚。我们首次证明脑缺血导致pMCAO后miR-182显著进行性增加，bEnd.3细胞是miR-182的主要靶细胞。在miR-182 KD转基因小鼠中，梗死体积和BBB通透性减弱，紧密连接（TJ）蛋白增加。用阿托莫西汀抑制miR-182减少了OGD诱导的bEnd.3细胞凋亡以及ZO-1和Occludin的丢失。为了进一步探索miR-182调节BBB完整性的机制，我们检测了凋亡蛋白Bcl-2/Bax，并证明mTOR和FOXO 1是miR-182的靶点。雷帕霉素/AS 1842856抑制mTOR/FOXO 1可降低Bcl-2/Bax比值，并加剧TJ蛋白丢失。总之，抑制miR-182通过mTOR/FOXO 1途径减少内皮细胞凋亡来保护BBB完整性。因此，miR-182可能是治疗脑缺血期间BBB破坏的潜在靶点。
Cerebral ischemia causes damage to the structure and function of the blood‐brain barrier (BBB) and alleviating BBB destruction will be of great significance for the treatment and prognosis of ischemic stroke. Recently, microRNAs have been shown to play a critical role in BBB integrity. However, the potential mechanism by which microRNA‐182 (miR‐182) affects the BBB in ischemic stroke remains unclear. We demonstrated for the first time that cerebral ischemia leads to a significant progressive increase in miR‐182 after pMCAO, and bEnd.3 cells are the primary target cells of miR‐182. In miR‐182 KD transgenic mice, infarct volume, and BBB permeability were attenuated, and tight junction (TJ) proteins increased. Inhibition of miR‐182 with an antagomir reduced OGD‐induced apoptosis of bEnd.3 cells and the loss of ZO‐1 and Occludin. To further explore the mechanism by which miR‐182 regulates BBB integrity, we detected the apoptotic proteins Bcl‐2/Bax and demonstrated that mTOR and FOXO1 were the targets of miR‐182. Inhibition of mTOR/FOXO1 by rapamycin/AS1842856 decreased the ratio of Bcl‐2/Bax and exacerbated TJ protein loss. Taken together, inhibition of miR‐182 protects BBB integrity by reducing endothelial cell apoptosis through the mTOR/FOXO1 pathway. Thus, miR‐182 may be a potential target for the treatment of BBB disruption during cerebral ischemia.