表观转录元件溴结构域蛋白4抑制剂减轻心肌梗死后心脏损伤  

Epigenetic transcription factor bromodomain-containing protein4 inhibitors reduce heart damage after myocardial infarction

作　　者：郭昱瑄 乔博康 王媛[1] 舒绍坤 杜杰[1] GUO Yuxuan;QIAO Bokang;WANG Yuan;SHU Shaokun;DU Jie(Department of Vascular Biology,Beijing Anzhen Hospital,Capital Medical University,Beijing Institute of Heart,Lung and Blood Vessel Diseases,Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院-北京市心肺血管疾病研究所,100029 [2]北京大学肿瘤医院

出　　处：《心肺血管病杂志》2024年第3期306-311,共6页Journal of Cardiovascular and Pulmonary Diseases

基　　金：国家自然科学基金(82200459,81930014);科技部国家重点研发计划(2021YFA0805102)。

摘　　要：目的:探究溴结构域蛋白4(bromodomain-containing protein 4,BRD4)在心肌梗死后心脏损伤中的作用。方法:通过分析公共数据,明确心肌梗死小鼠心脏组织中BRD4在整体和以及各细胞群中的表达变化。构建心肌梗死小鼠模型,设立空白对照组(WT组),心肌梗死组(MI组),药物组(JQ1组,ABBV-744组),术后第6天腹腔注射BRD4抑制剂JQ1或灌胃二代抑制剂ABBV-744,持续22天。MI术后4周,小动物超声影像系统检测小鼠心功能,检测小鼠质量、心脏质量与胫骨长度,天狼星红染色评估梗死区纤维化程度,WGA染色检测心肌细胞横截面积。结果:与心肌梗死组相比,BRD4抑制剂组能够显著改善术后心功能障碍(P<0.01)。转录组学数据表明,BRD4在心肌梗死损伤区域持续高表达。单细胞数据显示,心肌梗死后,成纤维细胞中BRD4阳性细胞比例显著增加,并且在心肌梗死后7、14、30d的成纤维细胞中,BRD4表达持续上调。与心肌梗死组相比,BRD4抑制剂组显著减轻心脏纤维化(P <0.01)。与一代药物组相比,二代药物组心脏纤维化程度显著降低(P<0.01)。结论:抑制表观转录因子BRD4可减轻心肌梗死后心脏损伤,抑制心脏纤维化,并改善心功能。Objective:To investigate the role of the bromodomain-containing protein 4(BRD4)in cardiac injury following myocardial infarction.Methods:By analyzing publicly available data,we aim to elucidate the changes of BRD4 in both the overall and individual cell populations within the heart tissue of mice after myocardial infarction.A myocardial infarction mouse model was established,including WT group,MI group,and drug treatment groups(JQ1 group,ABBV-744 group).On the 6th day post-myocardial infarction,mice in each group were subjected to intraperitoneal injection of the first-generation BRD4 inhibitor JQ1 or oral administration of the second-generation inhibitor ABBV-744,with the treatment sustained for 22 days.Four weeks post-myocardial infarction(MI)surgery,mouse cardiac function was assessed using a small animal ultrasound imaging system.Measurements included mouse body weight,heart mass,and tibia length.Sirius red staining was employed to evaluate the extent of fibrosis in the infarcted area,while WGA was utilized to assess the cross-sectional area of myocardial cells.Results:Compared to the myocardial infarction group,the BRD4 inhibitor groups both exhibit a significant improvement in postoperative cardiac dysfunction(P<0.01).Transcriptomic data indicates sustained high expression of BRD4 in the infarcted area.Single-cell data reveals a significant increase in the proportion of BRD4-positive cells within fibroblasts after myocardial infarction,and the expression of BRD4 continued to increase in fibroblasts at 7,14,and 30 days post-infarction.Compared to the MI group,both the BRD4 inhibitors reduce cardiac fibrosis(P<0.01).Additionally,the second-generation inhibitor group exhibit a significant decrease in cardiac fibrosis compared to the first-generation inhibitor group(P<0.01).Conclusions:Inhibiting the epigenetic transcription factor BRD4 can alleviate cardiac injury following myocardial infarction,suppress cardiac fibrosis,and improve cardiac function.

关 键 词：溴结构域蛋白4 表观调控 心脏成纤维细胞 心肌梗死 

分 类 号：R54[医药卫生—心血管疾病]