组蛋白去乙酰化酶11对乙肝病毒在小鼠体内复制的抑制作用  

Histone deacetylase 11 inhibits hepatitis B virus replication in mice

作　　者：夏剑波[1] 赵凯涛 吴小雪 杨曦 吴春晨 黎炎梅[3,4] Xia Jianbo;Zhao Kaitao;Wu Xiaoxue;Yang Xi;Wu Chunchen;Li Yanmei(Department of Laboratory Medicine,Maternal and Child Health Hospital of Hubei Province,Wuhan 430070,China;Institute of Medical Virology,State Key Laboratory of Virology,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,China;The Institute of Public Health And Safety Evaluation,Hubei Provincial Center for Disease Control and Prevention,Wuhan 430079,China;Hubei Provincial Key Laboratory for Applied Toxicology,Wuhan 430079,China)

机构地区：[1]湖北省妇幼保健院检验科,武汉430070 [2]武汉大学基础医学院医学病毒学研究所,430071 [3]湖北省疾病预防控制中心公共卫生安全评价研究所,武汉430079 [4]应用毒理湖北省重点实验室,武汉430079

出　　处：《中华实验外科杂志》2021年第10期1906-1908,共3页Chinese Journal of Experimental Surgery

基　　金：应用毒理湖北省重点实验室开放课题(AT2019-2)。

摘　　要：目的探讨组蛋白去乙酰化酶11(HDAC11)抗乙肝病毒(HBV)的体内效果和毒性。方法选取4~6周龄雄性C57BL/6 (H-2b)小鼠,通过尾静脉高压水注射法建立HBV体内复制模型。采用随机数表法分组方式分为5组:正常对照组,仅给予磷酸缓冲盐溶液(PBS)处理;模型组,仅注射HBV复制质粒;HDAC11低、中、高剂量组,在注射HBV复制质粒的同时分别给予2.5、5.0、10.0 μg/只小鼠剂量的HDAC11过表达质粒。于注射后第1、4、7、10、14天采集小鼠眼眶静脉血,通过化学发光微粒子免疫检测法分析血清中乙肝表面抗原(HBsAg)、e抗原(HBeAg)的水平;通过实时荧光定量聚合酶链反应(Real-time PCR)分析血清中HBV脱氧核糖核酸(DNA)的水平;通过免疫组织化学染色分析肝组织中核心抗原(HBcAg)的表达水平。采用Studentt检验或Mann-WhitneyU检验进行统计学分析。结果给药后第1天,HDAC11低、中、高剂量组的HBsAg水平均显著低于模型组[(165.99±50.35)比(238.69±31.99) IU/ml,t=3.498,P<0.01],[(89.92±34.55)比(238.69±31.99) IU/ml,t=8.937,P<0.01],[(26.56±19.45)比(238.69±31.99) IU/ml,t=16.027,P<0.01]。给药后第4天,HDAC11中、高剂量组的HBsAg水平仍显著低于模型组[(164.86±67.99)比(242.78±20.42) IU/ml,t=3.104,P<0.01],[(70.78±44.76)比(242.78±20.42) IU/ml,t=9.889,P<0.01]。给药后第1天,HDAC11中、高剂量组的HBeAg水平均显著低于模型组[(4.43±1.62)比(12.05±5.90),t=3.523,P<0.01],[(1.91±1.11)比(12.05±5.90),t=4.778,P<0.01]。给药后第4天,HDAC11低、中、高剂量组的HBV DNA水平显著低于模型组[(4.64±2.60)×10^(3)比(3.11±1.63)×10^(4) IU/ml,t=3.197,P<0.05],[(2.08±1.27)×10^(3)比(3.11±1.63)×10^(4) IU/ml,t=3.541,P<0.05],[(3.41±2.30)×10^(3)比(3.11±1.63)×10^(4) IU/ml,t=3.354,P<0.05]。肝组织中的HBcAg水平显著降低。给药组血清谷丙转氨酶、谷草转氨酶水平及动物体重等与对照组无明显差异。结论 HDAC11在体内具有显著的抗HBV复制的效果,且毒性较低�Objective To identify the anti-hepatitis B virus(HBV)effect and toxicity of histone deacetylase 11(HDAC11)in vivo.Methods HBV replication in vivo was established in male C57BL/6(H-2b)mice,aged 4-6 weeks,using hydrodynamic injection mice model.The mice were randomly divided into 5 groups:In normal control group,only phosphate buffer saline(PBS)were given.In model group,HBV replication-competent plasmid were given.In low,medium and high dose HDAC11 group,HBV replication-competent plasmid with 2.5,5.0 and 10.0μg HDAC11 overexpression plasmid per mice were given,respectively.At 1,4,7,10 and 14 days post hydrodynamic injection,Hepatitis B surface antigen(HBsAg)and e antigen(HBeAg)in the sera were detected by chemiluminescent immunoassay.HBV DNA in the sera were measured by real-time PCR assay.Intrahepatic hepatitis B core antigen(HBcAg)was detected by Immunohistochemical staining.Statistics were performed using the Student t-test or the nonparametric Mann-Whitney U test.Results At day 1 post hydrodynamic injection,the levels of HBsAg in low,medium and high dose HDAC11 group were significantly lower than that of the model group[(165.99±50.35)vs.(238.69±31.99)IU/ml,t=3.498,P<0.01],[(89.92±34.55)vs.(238.69±31.99)IU/ml,t=8.937,P<0.01],[(26.56±19.45)vs.(238.69±31.99)IU/ml,t=16.027,P<0.01].At day 4 post hydrodynamic injection,the levels of HBsAg in medium and high dose HDAC11 group were still significantly lower than that of the model group[(164.86±67.99)vs.(242.78±20.42)IU/ml,t=3.104,P<0.01],[(70.78±44.76)vs.(242.78±20.42)IU/ml,t=9.889,P<0.01].At day 1 post hydrodynamic injection,the levels of HBeAg in medium and high dose HDAC11 group were significantly lower than that of the model group[(4.43±1.62)vs.(12.05±5.90),t=3.523,P<0.01],[(1.91±1.11)vs.(12.05±5.90),t=4.778,P<0.01].At day 4 post hydrodynamic injection,the levels of HBV DNA in low,medium and high dose HDAC11 group were significantly lower than that of the model group[(4.64±2.60)×10^(3) vs.(3.11±1.63)×10^(4) IU/ml,t=3.197,P<0.05],[(2.08±1.27)×10

关 键 词：组蛋白去乙酰化酶 乙肝病毒 表观遗传学 抗病毒治疗 

分 类 号：R373.21[医药卫生—病原生物学]