MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral ischemia

  • FASEB J. 2020 Oct;34(10):13762-13775. doi: 10.1096/fj.201903092R.
Tongshuai Zhang  1  2 ,  Chao Tian  1  3 ,  Jinrong Wu  1  4 ,  Yao Zhang  1 ,  Jinghua Wang  1 ,  Qingfei Kong  1 ,  Lili Mu  1 ,  Bo Sun  1 ,  Tianhong Ai  1 ,  Yue Wang  1 ,  Wei Zhao  1 ,  Dandan Wang  5 ,  Hulun Li  1  2 ,  Guangyou Wang  1  2
Affiliations
  • 1. Department of Neurobiology, Harbin Medical University, Harbin, China.
  • 2. Ministry of Education Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Harbin, China.
  • 3. School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.
  • 4. Department of Anaesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 5. Wu Lian De Memorial Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
PMID: 32808351 DOI: 10.1096/fj.201903092R
Abstract

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.

Keywords
BBB; FOXO1; TJ proteins; mTOR; miR-182.
Products