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

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

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. z2jeffxu@zju.edu.cn.
  • 5 Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, Hangzhou, China. z2jeffxu@zju.edu.cn.
  • 6 Zhejiang Province Clinical Research Center for Emergency and Critical Care Medicine, Hangzhou, China. z2jeffxu@zju.edu.cn.
  • 7 Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. z2jzk@zju.edu.cn.
  • 8 Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, Hangzhou, China. z2jzk@zju.edu.cn.
  • 9 Zhejiang Province Clinical Research Center for Emergency and Critical Care Medicine, Hangzhou, China. z2jzk@zju.edu.cn.
  • # 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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