CHOP induces apoptosis by affecting brain iron metabolism in rats with subarachnoid hemorrhage

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The endoplasmic reticulum stress-related factor CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) aggravates early brain injury (EBI) in rats after subarachnoid hemorrhage (SAH). Our research aims to investigate the role of CHOP-mediated iron metabolism in EBI after SAH and the underlying mechanism. Male Sprague-Dawley rats were used to establish SAH models. Tunicamycin (Tm) was employed to excite CHOP expression, and two CHOP small interfering RNAs (siRNAs) were used to inhibit CHOP expression. Neurological scores, brain water content, and blood-brain barrier (BBB) permeability were evaluated at 24 h after SAH. Western blotting and immunofluorescence were implemented for the quantification and localization of GRP78 (glucoseregulated protein78), CHOP, C/EBPα (CCAAT/enhancer binding proteinα) and hepcidin. Apoptotic cells were detected by TUNEL staining, and the brain iron content was measured via Perls' staining. The expression of CHOP and hepcidin increased and the expression of C/EBPα decreased after SAH. Knockdown of CHOP decreased the brain water content, reduced Evans blue extravasation, and improved neurological functions. CHOP significantly increased hepcidin levels and significantly decreased C/EBPα levels after SAH. Hepcidin is expressed in the nuclei of neurons and is widely co-localized with TUNEL-positive cells both in the hippocampus and cortex. Along with increased hepcidin expression, the iron content in brain tissue and the apoptosis rate were increased. Thus, CHOP promotes hepcidin expression by regulating C/EBPα activity, which increases the brain iron content, induces apoptosis and is involved in the development of EBI after SAH.HIGHLIGHTSThe presence and important role of the CHOP in the occurrence of EBI after SAH is confirmed.CHOP induces apoptosis by affecting brain iron metabolism after SAH.The mechanism relies on CHOP-C/EBPα-hepcidin signaling pathway.

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