Department of Neurology and Stroke Center, The First Affiliated Hospital, & Clinical Neuroscience Institute of Jinan University, 613 West Huangpu Ave, Guangzhou 510632, China; Affiliated Hospital of Guangdong Medical University, 57 South Renmin Ave, Zhanjiang 524001, China.
Department of Neurology and Stroke Center, The First Affiliated Hospital, & Clinical Neuroscience Institute of Jinan University, 613 West Huangpu Ave, Guangzhou 510632, China.
Mol Ther. 2022 Mar 2;30(3):1275-1287. doi: 10.1016/j.ymthe.2021.11.004. Epub 2021 Nov 8.
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.
血脑屏障（BBB）损伤可能是中枢神经系统（CNS）疾病的结果，并且可能是 CNS 恶化的原因。然而，在缺血/再灌注（I / R）损伤期间维持 BBB 完整性的有效和靶向治疗方法仍有许多未知。在这项研究中，我们证明 FoxO3 的环状 RNA（circ-FoxO3）通过抑制 mTORC1 促进自噬，从而减轻 I / R 下的 BBB 崩溃。在出血性转化的患者的脑微血管内皮细胞和大脑中动脉闭塞/再灌注的小鼠模型中均检测到 circ-FoxO3 和自噬流的上调。体内和体外研究表明，circ-FoxO3 主要通过自噬激活来减轻 BBB 损伤。在机制上，我们发现 circ-FoxO3 主要通过隔离 mTOR 和 E2F1 来抑制 mTORC1 活性，从而促进自噬以清除细胞毒性聚集体，从而改善 BBB 完整性。这些结果表明 circ-FoxO3 在保护 BBB 损伤方面发挥了新的作用，并且 circ-FoxO3 可能是与 BBB 损伤相关的神经障碍的有前途的治疗靶标。
