2. Academic Validation
  3. Hemorrhagic shock and reperfusion induced cognitive impairment through HIF3α/SIRT1

Hemorrhagic shock and reperfusion induced cognitive impairment through HIF3α/SIRT1

  • Free Radic Biol Med. 2025 Aug 15:240:491-503. doi: 10.1016/j.freeradbiomed.2025.08.029.
Song Xue 1,  Jinyan Wang 1,  Yao Tian 2,  Tianyu Zong 1,  Yan Zhang 3,  Xin Zhou 1,  Mengyi Li 1,  Shuwen He 1,  Wei Yan 4,  Ye Zhang 5,  Xianwen Hu 6,  Chunxia Huang 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230601, China.
  • 2 Daping Hospital, Army Medical University, Chongqing, 400042, China.
  • 3 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230601, China; Wuhu Maternal and Child Health Hospital, Wuhu, 241000, China.
  • 4 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China. Electronic address: weiyan@bjmu.edu.cn.
  • 5 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230601, China. Electronic address: zhangy@ahmu.edu.cn.
  • 6 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230601, China. Electronic address: huxianwen001@126.com.
  • 7 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230601, China; Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China. Electronic address: huangchunxia@ahmu.edu.cn.
PMID: 40819662 DOI: 10.1016/j.freeradbiomed.2025.08.029
Abstract

Cerebral ischemia-reperfusion induces hippocampal neuronal Apoptosis, resulting in cognitive impairment. Hypoxia-inducible factor 3α (HIF3α), a transcription factor involved in Apoptosis, plays a crucial role in multiple cognitive disorders. However, the role of HIF3α in cerebral ischemia-reperfusion remains unclear. In this study, we employed an in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R) and a hemorrhagic shock and reperfusion (HSR) model to simulate cerebral ischemia-reperfusion injury (CIRI). Both models demonstrated high co-localization of SIRT1 and HIF3α in hippocampal neurons, as well as increased expression of phosphorylated Tau Protein and neuronal Apoptosis. siRNA-mediated knockdown of HIF3α downregulated SIRT1 protein expression in hippocampal neurons subjected to OGD/R, whereas pharmacological inhibition or gene knockdown of SIRT1 did not alter HIF3α levels. HIF3α knockdown also enhanced the antioxidant response, and attenuated OGD/R-induced Autophagy, phosphorylated Tau Protein expression and neuronal Apoptosis in vitro. Notably, OGD/R promoted Autophagy in hippocampal neurons, while Autophagy inhibition by 3-MA decreased phosphorylated tau expression and neuronal Apoptosis after OGD/R. Consistent with the results of the in vitro experiments, HIF3α knockout reduced SIRT1 and LC3B protein levels, decreased phosphorylated tau expression and improved hippocampal neuronal Apoptosis and synaptic loss, thereby ameliorating cognitive deficits following HSR. Collectively, our findings reveal that HIF3α exacerbates CIRI-related cognitive impairment by promoting SIRT1-dependent Autophagy, resulting in hippocampal neuronal Apoptosis.

Keywords

Apoptosis; Autophagy; Cognitive impairment; HIF3α; Hemorrhagic shock and reperfusion; Oxygen-glucose deprivation/reoxygenation; SIRT1.

Figures
Products