Circular RNA circ-FoxO3 attenuates blood-brain barrier damage by inducing autophagy during ischemia/reperfusion

作者：Zhenguo Yang, Cheng Huang, Xueyi Wen, Wenlin Liu, Xiao-Xiong Huang, Yufeng Li, Jiankun Zang, Zean Weng, Dan Lu, Chi Kwan Tsang, Keshen Li, Anding Xu · 发表于：Molecular Therapy · 年份：2021 · DOI：10.1016/j.ymthe.2021.11.004 · 被引用次数：120 · 研究领域：Circular RNAs in diseases、MicroRNA in disease regulation、Cancer-related molecular mechanisms research

Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration. However, there are still many unknowns regarding effective and targeted therapies for maintaining BBB integrity during ischemia/reperfusion (I/R) injury. In this study, we demonstrate that the circular RNA of FoxO3 (circ-FoxO3) promotes autophagy via mTORC1 inhibition to attenuate BBB collapse under I/R. Upregulation of circ-FoxO3 and autophagic flux were detected in brain microvessel endothelial cells in patients with hemorrhagic transformation and in mice models with middle cerebral artery occlusion/reperfusion. In vivo and in vitro studies indicated that circ-FoxO3 alleviated BBB damage principally by autophagy activation. Mechanistically, we found that circ-FoxO3 inhibited mTORC1 activity mainly by sequestering mTOR and E2F1, thus promoting autophagy to clear cytotoxic aggregates for improving BBB integrity. These results demonstrate that circ-FoxO3 plays a novel role in protecting against BBB damage, and that circ-FoxO3 may be a promising therapeutic target for neurological disorders associated with BBB damage.