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.
摘要：
心脏骤停（CA）和心肺复苏（CPR）后的脑损伤是导致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)在大鼠CA/CPR后神经功能恢复中的作用机制。通过CA/CPR治疗建立大鼠模型。将腺病毒包装的sh-HDAC6注射到尾静脉中。评价大鼠的神经功能,生存时间,神经功能评分,血清NSE/S100B,测定脑含水量，进行Morris水迷宫试验。HDAC6,microRNA(miR)-138-5p,Nod样受体蛋白3（NLRP3），并通过实时定量聚合酶链反应或Westernblot测定促性腺激素水平。通过染色质免疫沉淀检查miR-138-5p启动子上的HDAC6和H3K9ac富集。通过双荧光素酶报告基因测定分析miR-138-5p-NLRP3结合。NLRP3炎性体用尼日利亚霉素钠盐活化。CPR治疗后,HDAC6高表达，而miR-138-5p下调。HDAC6下调改善了神经功能并减少了焦亡。HDAC6在miR-138-5p启动子脱乙酰H3K9ac上的富集，抑制miR-138-5p，并促进NLRP3介导的焦亡。下调miR-138-5p部分逆转了CPR后HDAC6抑制的保护作用。在结论中,HDAC6在miR-138-5p启动子脱乙酰H3K9ac上的富集，抑制miR-138-5p表达并促进NLRP3介导的焦亡，心肺复苏后大鼠神经功能障碍恶化。
