Apelin-13 Alleviates Early Brain Injury after Subarachnoid Hemorrhage via Suppression of Endoplasmic Reticulum Stress-mediated Apoptosis and Blood-Brain Barrier Disruption: Possible Involvement of ATF6/CHOP Pathway.

Neuronal apoptosis plays important roles in the early brain injury after subarachnoid hemorrhage (SAH). This study first showed that inhibition of activating transcription factor 6 (ATF6) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-mediated apoptosis and blood-brain-barrier (BBB) disruption after SAH. We chose apelin-13, ATF6 and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) siRNAs to verify the hypothesis. Brain water content, neurological behavior and Evans Blue (EB) were assessed at 24 h after SAH. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were applied to evaluate the expression of targets in both protein and mRNA levels. Neuronal apoptosis was assessed with Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) and caspase-3 staining. The results showed that the levels of ATF6, and its downstream protein, CHOP were upregulated and reached the peak at 24 h after SAH. ATF6 was highly expressed in neurons. The administration of apelin-13 could significantly reduce the mRNA and protein levels of ATF6, and its downstream targets, CHOP and caspase-3, but increase the Bcl-2/Bax ratio, Claudin-5, Occludin and ZO-1. What's more, the administration of apelin-13 could reduce brain edema, ameliorate BBB disruption and improve neurological functions. However, the CHOP siRNA could significantly reverse the pro-apoptotic effect induced by the increased ATF6 level after SAH. Apelin-13 could exert its neuroprotective effects via suppression of ATF6/CHOP arm of ER-stress-response pathway in the early brain injury after SAH.