Department of Infectious Diseases, Minhang Hospital, Fudan University, Shanghai 201199, China.
Department of Critical Care Medicine, Minhang Hospital, Fudan University, Shanghai 201199, China.
Brain Res. 2024 Nov 15;1843:149121. doi: 10.1016/j.brainres.2024.149121. Epub 2024 Jul 10.
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.
心脏骤停（CA）和心肺复苏（CPR）后的脑损伤是神经功能障碍和死亡的主要原因。本研究旨在探讨组蛋白去乙酰化酶 6（HDAC6）在 CA/CPR 后大鼠神经功能恢复中的作用机制。通过 CA/CPR 处理建立大鼠模型。尾静脉注射腺病毒包装的 sh-HDAC6。为评估大鼠的神经功能，测量生存时间、神经功能评分、血清 NSE/S100B 和脑水含量，并进行 Morris 水迷宫测试。通过实时定量聚合酶链反应或 Western blot 测定 HDAC6、微小 RNA（miR）-138-5p、Nod 样受体蛋白 3（NLRP3）和细胞焦亡因子水平。通过染色质免疫沉淀检测 miR-138-5p 启动子上的 HDAC6 和 H3K9ac 富集。通过双荧光素酶报告基因检测分析 miR-138-5p-NLRP3 结合。用硝普酸钠激活 NLRP3 炎症小体。CPR 治疗后，HDAC6 高表达，而 miR-138-5p 下调。HDAC6 下调改善神经功能并减少细胞焦亡。HDAC6 在 miR-138-5p 启动子上的富集使 H3K9ac 去乙酰化，抑制 miR-138-5p，促进 NLRP3 介导的细胞焦亡。下调 miR-138-5p 部分逆转了 CPR 后 HDAC6 抑制的保护作用。总之，HDAC6 在 miR-138-5p 启动子上的富集使 H3K9ac 去乙酰化，抑制 miR-138-5p 的表达并促进 NLRP3 介导的细胞焦亡，加重 CPR 后大鼠的神经功能障碍。
