Acetyl-CoA synthetase 2 alleviates brain injury following cardiac arrest by promoting autophagy in brain microvascular endothelial cells.

INTRODUCTION

Brain injury is a common sequela following cardiac arrest (CA), with up to 70% of hospitalized patients dying from it. Brain microvascular endothelial cells (BMVECs) play a crucial role in post-cardiac arrest brain injury (PCABI). However, the effects and mechanisms of targeting BMVEC energy metabolism to mitigate brain injury remain unclear.

METHODS

We established a mouse model of cardiac arrest by injecting potassium chloride into the right internal jugular vein. Mass spectrometry detected targeted changes in short-chain fatty acids and energy metabolism metabolites in the CA/CPR group compared to the sham group. Mice with overexpressed ACSS2 in BMVECs were created using an AAV-BR1 vector, and ACSS2 knockout mice were generated using the CRE-LOXP system. The oxygen glucose deprivation/re-oxygenation (OGD/R) model was established to investigate the role and mechanisms of ACSS2 in endothelial cells in vitro.

RESULTS

Metabolomics analysis revealed disrupted cerebral energy metabolism post-CA/CPR, with decreased acetyl-CoA and amino acids. Overexpression of ACSS2 in BMVECs increased acetyl-CoA levels and improved neurological function. Vascular endothelial cell-specific ACSS2 knockout mice exhibited reduced aortic sprouting in vitro. Overexpression of ACSS2 improved endothelial dysfunction following oxygen glucose deprivation/re-oxygenation (OGD/R) and influenced autophagy by interacting with transcription factor EB (TFEB) and modulating the AMP-activated protein kinase α (AMPKα) pathway.

CONCLUSION

Our study shows that ACSS2 modulates the biological functions of BMVECs by promoting autophagy. Enhancing energy metabolism via ACSS2 may target PCABI treatment development.