Molecular mechanism of HDAC6-mediated pyroptosis in neurological function recovery after cardiopulmonary resuscitation in rats

  • Brain Res. 2024 Jul 10:1843:149121. doi: 10.1016/j.brainres.2024.149121.
Chunyan Chen  1 ,  Zhuye Xia  2 ,  Min Zhang  3 ,  Yunshan Cao  4 ,  Qingling Chen  5 ,  Qinglian Cao  5 ,  Xiang Li  2 ,  Fan Jiang  6
Affiliations
  • 1. Department of Infectious Diseases, Minhang Hospital, Fudan University, Shanghai 201199, China.
  • 2. Department of Critical Care Medicine, Minhang Hospital, Fudan University, Shanghai 201199, China.
  • 3. Department of Pathology, Gansu Provincial Hospital, Lanzhou 730000, China.
  • 4. Department of Cardiology, Gansu Provincial Hospital, Lanzhou 730000, China.
  • 5. Department of Emergency Medicine, Minhang Hospital, Fudan University, Shanghai 201199, China.
  • 6. Department of Emergency Medicine, Minhang Hospital, Fudan University, Shanghai 201199, China. Electronic address: [email protected].
PMID: 38997102 DOI: 10.1016/j.brainres.2024.149121
Abstract

Brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is the leading cause of neurological dysfunction and death. This study aimed to explore the mechanism of histone deacetylase 6 (HDAC6) in neurofunctional recovery following CA/CPR in rats. A rat model was established by CA/CPR treatment. Adenovirus-packaged sh-HDAC6 was injected into the tail vein. To evaluate the neurofunction of rats, survival time, neurofunctional scores, serum NSE/S100B, and brain water content were measured and Morris water maze test was performed. HDAC6, MicroRNA (miR)-138-5p, NOD-like Receptor protein 3 (NLRP3), and pyroptotic factor levels were determined by real-time quantitative polymerase chain reaction or Western blot assay. HDAC6 and H3K9ac enrichment on miR-138-5p promoter were examined by chromatin immunoprecipitation. miR-138-5p-NLRP3 binding was analyzed by dual-luciferase reporter assay. NLRP3 inflammasome was activated with nigericin sodium salt. After CPR treatment, HDAC6 was highly expressed, while miR-138-5p was downregulated. HDAC6 downregulation improved neurofunction and reduced Pyroptosis. HDAC6 enrichment on the miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p, and promoting NLRP3-mediated Pyroptosis. Downregulating miR-138-5p partially reversed the protective effect of HDAC6 inhibition after CPR. In Conclusion, HDAC6 enrichment on miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p expression and promoting NLRP3-mediated Pyroptosis, worsening neurological dysfunction in rats after CPR.

Keywords
Cardiopulmonary resuscitation; H3K9ac; HDAC6; NLRP3; Pyroptosis; miR-138-5p.
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