ACE2 Rescues Impaired Autophagic Flux Through the PI3K/AKT Pathway After Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is one of the life-threatening neurosurgical diseases in central nervous system. Autophagy has been previously demonstrated to exert vital roles in SAH development. Angiotensin I converting enzyme 2 (ACE2) has been revealed as a regulator of autophagy in neurosurgical diseases. However, effect of ACE2 on autophagy in SAH progression has not been clarified. First, we explored the relationship between autophagy and SAH progression by establishing a mouse model of SAH under the administration of 3-MA (the autophagy inhibitor). Next, we examined ACE2 expression in the cerebral cortex of SAH mice ex vivo with RT-qPCR. Subsequently, we assessed the biological function of ACE2 on brain injury, the autophagic flux pathway and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling ex vivo via neurological scoring, TUNEL assay, western blot analysis and immunofluorescence staining assay. Finally, we carried out rescue assays under chloroquine (CQ, the autophagic flux inhibitor) and LY294002 (the PI3K/AKT signaling inhibitor) administration. 3-MA mitigated brain injury after SAH, and ACE2 was downregulated in cerebral cortex of SAH mice. Moreover, ACE2 elevation alleviated cell apoptosis, cerebral edema, and neurological deficits, ameliorated the autophagic flux pathway and activated the PI3K/AKT signaling in SAH mice. Furthermore, CQ and LY294002 neutralized the effects of overexpressed ACE2 on neuronal apoptosis, cerebral edema, and neurological deficits in SAH mice. Overall, ACE2 lessened neuronal injury via the autophagic flux and PI3K/AKT pathways. This research might provide a potential novel direction for clinical treatment of SAH.