EFFECT AND REGULATORY MECHANISM OF SIRT6 ON POSTCARDIAC ARREST BRAIN INJURY IN RATS

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Brain injury is a primary cause of death and disability following cardiac arrest (CA) and successful cardiopulmonary resuscitation (CPR).
• Understanding the molecular mechanisms underlying post-cardiac arrest brain injury is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role and mechanism of Sirtuin 6 (SIRT6) in mitigating brain injury after CA and CPR in a rat model.
• To elucidate the relationship between SIRT6 and FOXO1 in the context of post-cardiac arrest brain injury.

Main Methods:

• Rats underwent asphyxial CA followed by CPR, with interventions involving lentiviral vectors to modulate SIRT6 and FOXO1 expression.
• Quantitative real-time PCR and Western blot were used to assess gene and protein expression.
• Neurological deficit scores, Water Maze Test, H&E staining, ELISA, TUNEL assay, and Chromatin Immunoprecipitation (ChIP) were employed to evaluate brain function, pathology, inflammation, apoptosis, and molecular interactions.

Main Results:

• SIRT6 expression was decreased, while FOXO1 expression was increased in rats subjected to CA/CPR.
• Overexpression of SIRT6 significantly improved neurological function, cognitive abilities, and survival rates in CA/CPR rats.
• SIRT6 suppressed FOXO1 transcription and expression by reducing H3K9ac levels at the FOXO1 promoter, and FOXO1 overexpression counteracted SIRT6's protective effects.

Conclusions:

• SIRT6 plays a protective role against brain injury following CA/CPR in rats.
• SIRT6 mitigates post-cardiac arrest brain injury by inhibiting FOXO1 expression via epigenetic modification of the FOXO1 promoter.
• Targeting SIRT6 may represent a therapeutic strategy for managing brain injury after cardiac arrest.