This is because autophagy eliminates the damaged organelles and proteins, and converts them into nutrients for promoting cell survival in various pathological processes. Autophagy is originally considered a self-protective mechanism of cells to overcome the injury from external stimuli. Intriguingly, recent literature has shown that circRNAs interact with autophagy-related miRNAs 11, 12 or proteins 13 for regulation of different pathological processes. Although many circRNAs are associated with CNS disorders, their involvement in neurovascular integrity and pathological processes require further investigation. 10 This indicated that some of the blood circRNAs might function as biomarkers for ischemic stroke. 9 Our previous study revealed that the number of circRNAs was differentially expressed in the blood of mice after middle cerebral artery occlusion (MCAO) and in patients with acute ischemic stroke. 7 Notably, circRNAs protect BBB integrity by targeting miRNAs against ischemic stroke 8 and bacterial meningitis. 5 These molecules take part in neurovascular functions, such as neurodevelopment 6 and degenerative diseases. 4 Recently, multiple circRNAs have been reported to be abundantly expressed in the brain. This is mainly due to their covalently closed loops, which help them resist degradation by RNase, and effectively maintain their biological functions. 3 Although the function of circRNAs is still not fully understood, they are known to exert a role in sequestering microRNAs (miRNAs) or RNA-binding proteins (RBPs) to undergo transcriptional and post-transcriptional regulation. Due to the critical role of BBB in cerebral protection, a thorough understanding of the endogenous mechanisms for maintaining BBB integrity may be a potential therapeutic strategy for treating neurological disorders including stroke.Ĭircular RNAs (circRNAs) endogenously express non-coding RNAs, and serve as biomarkers for multiple disorders. This increases BBB permeability, which makes it difficult to avoid secondary brain damage after reperfusion therapy. 2 In the pathological process of ischemic stroke, failure of blood flow caused by sudden blood vessel occlusion results in shrinkage of the BMECs, which causes translocation of tight junction proteins (TJs) from the membrane into the cytosol. 1 BBB disruption can occur as the result of CNS diseases and may be the cause of secondary brain injuries, including hemorrhage and brain edema. The BBB is generally considered to be the gatekeeper that helps to maintain the fragile homeostasis of the central nervous system (CNS) through segregation from the systemic circulation. The blood-brain barrier (BBB) is a highly organized multicellular structure composed of capillaries formed by self-fusion of brain microvascular endothelial cells (BMECs) through intact tight junctions, as well as peripheral pericytes and astrocytes surrounding the capillaries. 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. 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. In vivo and in vitro studies indicated that circ-FoxO3 alleviated BBB damage principally by autophagy activation. 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 this study, we demonstrate that the circular RNA of FoxO3 (circ-FoxO3) promotes autophagy via mTORC1 inhibition to attenuate BBB collapse under I/R. However, there are still many unknowns regarding effective and targeted therapies for maintaining BBB integrity during ischemia/reperfusion (I/R) injury. Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration.
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