溴结构域蛋白4抑制剂JQ1在急性心肌梗死中的作用及机制研究  

Role and mechanism of the inhibitor of bromodomain protein 4 JQ1 in acute myocardial infarction

作　　者：刘雨婷 邱宏亮 车妍[1] 唐其柱[1] LIU Yuting;QIU Hongliang;CHE Yan;TANG Qizhu(Dept.of Cardiovascular Medicine,Renmin Hospital of Wuhan University&Hubei Provincial Key Laboratory of Metabolism and Related Chronic Diseases,Wuhan 430060,Hubei,China)

机构地区：[1]武汉大学人民医院心血管内科/代谢与相关慢病湖北省重点实验室,湖北武汉430060

出　　处：《武汉大学学报(医学版)》2025年第1期1-7,共7页Medical Journal of Wuhan University

基　　金：国家自然科学基金区域创新发展联合基金项目(编号:U22A20269);国家重点研发计划资助项目(编号:2018YFC1311300)。

摘　　要：目的:探究溴结构域蛋白4(BRD4)抑制剂JQ1在急性心肌梗死(心梗,AMI)中的作用及机制。方法:(1)动物模型:C57BL/6J雄性小鼠通过冠状动脉前降支(LAD)结扎手术构建MI模型。JQ1溶入相应载体溶剂(DMSO∶10%β-环糊精=1∶4),术后2周隔日以50 mg/kg浓度腹腔注射,小鼠随机分为4组:对照+溶剂组、对照+JQ1组、心梗+溶剂组、心梗+JQ1组,每组6只。造模终点取小鼠心脏和血清作病理和生化分析。测量心脏大体和心功能指标;HE染色观察心肌形态学变化;DHE染色检测心肌ROS水平;ELISA检测心肌组织炎症和氧化应激水平;RT-PCR和Western Blot检测心肌损伤和氧化应激水平。(2)细胞模型:分离和培养原代新生大鼠心肌细胞(NRCMs),经过氧化氢(H2O2,150μmol/L)刺激12 h构建细胞氧化应激损伤模型,对照组使用等量PBS,JQ1以0.5μmol/L浓度溶于0.1%DMSO中,细胞分为4组:PBS组、PBS+JQ1组、H2O2组、H2O2+JQ1组。Western Blot检测胞质氧化应激相关蛋白水平和细胞核Nrf2表达水平。结果:(1)动物实验结果:JQ1治疗显著改善心肌损伤和炎症反应(P<0.05)。JQ1治疗逆转心梗小鼠心功能恶化和心脏结构紊乱(P<0.05)。JQ1治疗缓解心梗小鼠的心脏氧化应激水平(P<0.05)。(2)细胞实验结果:JQ1减轻H2O2诱导的心肌细胞氧化应激损伤,提高心肌抗氧化的水平。机制上,JQ1可上调细胞核Nrf2的蛋白水平,促进Nrf2的核转位和下游抗氧化基因的表达。结论:JQ1通过靶向Nrf2-Keap1通路,改善急性心肌梗死的心肌损伤、炎症反应和氧化应激损伤。Objective:To explore the role and mechanism of bromodomain-containing protein 4(BRD4)inhibitor JQ1 in acute myocardial infarction(AMI).Methods:(1)In vivo model:MI model was established in C57BL/6J male mice through anterior descending coronary artery(LAD)ligation surgery.JQ1 was dissolved into the corresponding carrier solvent(DMSO∶10%β-cyclodextrin=1∶4)and injected intraperitoneally at a concentration of 50 mg/kg every other day 2 weeks after surgery.The mice were randomly divided into 4 groups:control+solvent group,control+JQ1 group,myocardi al infarction+solvent group,and myocardial infarction+JQ1 group,with 6 animals in each group.Mouse hearts and serum samples were collected for pathological and biochemical analysis.The gross cardiac and cardiac function indicators were measured;HE staining was used to observe myocardial morphological changes;DHE staining was used to detect myocardial ROS levels;ELISA was used to detect myocardial tissue inflammation and oxidative stress levels;RT-PCR and Western Blot were used to detect myocardial damage and oxidative stress levels.(2)In vitro model:Primary newborn rat cardiomyocytes(NRCMs)were isolated cultured and stimulated with hydrogen oxide(H2O2,150μmol/L)for 12 hours to construct a cell oxidative stress injury model.An equal amount of PBS was used in the control group,and JQ1 was dissolved in 0.1%DMSO at a concentration of 0.5μmol/L,so the cells were divided into 4 groups:PBS group,PBS+JQ1 group,H2O2 group,H2O2+JQ1 group.Western Blot was adopted to detect the cytoplasmic oxidative stress-related proteins'levels and nuclear Nrf2 expression levels.Results:(1)In vivo model:JQ1 treatment significantly improved myocardial damage and inflammatory response,reversed the deterioration of cardiac function and cardiac structural disorder in mice with MI and alleviated cardiac oxidative stress levels in mice with MI(P<0.05).(2)In vitro model:JQ1 reduced H2O2-induced oxidative stress damage in cardiomyocytes(P<0.05).Mechanistically,JQ1 can upregulate the protein level of N

关 键 词：急性心肌梗死 JQ1 NRF2 氧化应激 炎症反应 

分 类 号：R54[医药卫生—心血管疾病]