期刊
FASEB JOURNAL
卷 34, 期 10, 页码 13762-13775出版社
WILEY
DOI: 10.1096/fj.201903092R
关键词
BBB; FOXO1; miR-182; mTOR; TJ proteins
资金
- National Natural Science Foundation of China [31671112, 31371079, 81070943, 31900697]
- Natural Science Foundation of Heilongjiang Province of China [QC2017087]
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.
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