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

  • Cell Mol Life Sci. 2025 Apr 17;82(1):160. doi: 10.1007/s00018-025-05689-7.
Wenbin Zhang  #  1  2  3 ,  Xin Yu  #  1  2  3 ,  Yao Lin  #  1  2  3 ,  Chenghao Wu  1  2  3 ,  Ruojie Zhu  1  2  3 ,  Xiangkang Jiang  1  2  3 ,  Jiawei Tao  1  2  3 ,  Ziwei Chen  1  2  3 ,  Jiantao He  1  2  3 ,  Xiaodan Zhang  1  2  3 ,  Jiefeng Xu  4  5  6 ,  Mao Zhang  7  8  9
Affiliations
  • 1. Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, Hangzhou, China.
  • 3. Zhejiang Province Clinical Research Center for Emergency and Critical Care Medicine, Hangzhou, China.
  • 4. Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 5. Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, Hangzhou, China. [email protected].
  • 6. Zhejiang Province Clinical Research Center for Emergency and Critical Care Medicine, Hangzhou, China. [email protected].
  • 7. Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 8. Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, Hangzhou, China. [email protected].
  • 9. Zhejiang Province Clinical Research Center for Emergency and Critical Care Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 40244361 DOI: 10.1007/s00018-025-05689-7
Abstract

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.

Keywords
ACSS2; Autophagy; Cardiopulmonary resuscitation; Endothelial dysfunction; Ischemia-reperfusion injury.
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