Effect and regulatory mechanism of SIRT6 on post-cardiac arrest brain injury in rats.

Aims: Brain injury occupies the predominant cause of neurological dysfunction and mortality after successful cardiopulmonary resuscitation (CPR) from cardiac arrest (CA). This study investigates the role and mechanism of Sirtuin 6 (SIRT6) in post-cardiac arrest brain injury in rats.

Methods: All rats were subjected to asphyxial CA followed by CPR. Two weeks before modeling, rats were infected with lentivirus containing oe-SIRT6 and oe-FOXO1 through lateral ventricular injection. qRT-PCR and Western blot quantified SIRT6 and FOXO1 expressions in brain tissues. Neurological deficit scores evaluated the neural function of rats at different time points, and water maze test assessed the changes in short-term learning and memory abilities. The survival status of rats 7 days after modeling was recorded. The pathological changes in brain tissues, inflammatory factors, and apoptosis were evaluated by H&E staining, ELISA, and TUNEL, respectively. Ch-IP measured the enrichment of SIRT6 and H3K9ac in the FOXO1 promoter.

Results: SIRT6 was poorly expressed while FOXO1 was highly expressed in CA/CPR rats. Elevation of SIRT6 expression alleviated neural function, behavioral ability, and survival rate, as well as abated pathological damage, inflammatory responses, and cell apoptosis in CA/CPR rats. Mechanistically, SIRT6 curbed FOXO1 transcription and expression by lowering the H3K9ac level in the FOXO1 promoter; FOXO1 overexpression abolished the improvement effect of SIRT6 overexpression on brain injury in CA/CPR rats.

Conclusions: Elevation of SIRT6 expression restrained the FOXO1 expression by diminishing the H3K9ac level in the FOXO1 promoter, thereby mitigating post-cardiac arrest brain injury in rats.