组蛋白去乙酰化酶4抑制肌细胞增强因子2C介导的肺动脉高压小鼠肺血管重构研究  

Histone Deacetylase 4 Inhibits Pulmonary Vascular Remodeling Mediated by Myocyte Enhancer Factor 2C in Mice with Pulmonary Arterial Hypertension

作　　者：曾军[1] 周夏飞[1] 张维[1] Zeng Jun;Zhou Xiafei;Zhang Wei(Department of Respiratory and Critical Care Medicine,The First Affiliated Hospital of Chengdu Medical College,Chengdu 610500,China)

机构地区：[1]成都医学院第一附属医院呼吸与危重症医学科,成都610500

出　　处：《成都医学院学报》2021年第6期688-693,共6页Journal of Chengdu Medical College

基　　金：国家自然科学基金(No:81600388)。

摘　　要：目的观察经组蛋白去乙酰化酶4抑制剂(HDAC4i)处理后小鼠肺组织中组蛋白去乙酰化酶4(HDAC4)、肌细胞增强因子2C(MEF2C) mRNA及其蛋白表达水平变化,以及小鼠肺血管的病理生理改变,探讨HDAC4是否调节MEF2C介导的肺动脉平滑肌细胞增殖。方法健康雄性BALB/C小鼠32只,随机分为肺动脉高压模型(PAH)组(野百合碱处理)、HDAC4i组(HDAC4i处理)、PAH+HDAC4i组(野百合碱联合HDAC4i处理)及阴性对照组(NC组)4组,每组8只。在第2周、第4周监测4组小鼠肺动脉血流动力学改变、右心室肥厚指数[RV/(LV+S)],采用荧光定量PCR与蛋白质印迹技术检测小鼠肺组织MEF2C mRNA及其蛋白表达水平变化,采用免疫组化检测小鼠肺组织α-平滑肌肌动蛋白(α-SMA)、骨桥蛋白(OPN)及HDAC4蛋白表达及定位。结果第2周和第4周,PAH组、PAH+HDAC4i组及HDAC4i组小鼠RV/(LV+S)均明显高于NC组(P<0.01);PAH组、PAH+HDAC4i组及HDAC4i组小鼠右心室收缩压(RVSP)均明显高于NC组(P<0.01)。与NC组比较,第4周PAH组、PAH+HDAC4i组及HDAC4i组MEF2C mRNA及其蛋白表达量均升高,且MEF2C mRNA表达差异有统计学意义(P<0.05)。免疫组化显示:与NC组比较,PAH组、PAH+HDAC4i组及HDAC4i组小鼠肺动脉平滑肌细胞呈现OPN表达水平上升,而α-SMA与HDAC4蛋白表达水平明显下降。结论 HDAC4抑制MEF2C介导的肺动脉高压小鼠肺血管重构。Objective To observe the changes of histone deacetylase 4(HDAC4), myocyte enhancer factor 2 C(MEF2C) mRNA and it’s protein expression in lung tissues, as well as the pathophysiological changes in lung vessels of mice after HDAC4 inhibitor(HDAC4 i) treatment, so as to investigate whether HDAC4 regulates the proliferation of pulmonary artery smooth muscle cells mediated by MEF2C. Methods A total of 32 healthy male BALB/C mice were randomly divided into 4 groups: pulmonary arterial hypertension(PAH) model group(n=8, treated by monocrotaline), HDAC4 i group(n=8, treated by HDAC4 i), PAH+HDAC4 i group(n=8, treated by monocrotaline combined with HDAC4 i), and negative control(NC) group(n=8). At the 2 nd and 4 th week, hemodynamics changes in pulmonary artery and right ventricular hypertrophy index [RV/(LV+S)] of mice in the 4 groups were monitored. The MEF2C mRNA and it’s protein expression in lung tissues of mice were detected by quantitative reverse transcription polymerase chain reaction(qRT-PCR) and Western blot. The protein expression and localizaton of α-smooth muscle actin(α-SMA), osteopontin(OPN) and HDAC4 in lung tissues of mice were detected by immunohistochemical staining. Results RV/(LV+S) in PAH group, PAH+HDAC4 i group and HDAC4 i group was significantly higher than that in NC group at the 2 nd and 4 th week(P<0.01). Right ventricular systolic pressure(RVSP) in PAH group, PAH+HDAC4 i group and HDAC4 i group was significantly higher than that in NC group at the 2 nd and 4 th week(P<0.01). Compared with NC group, MEF2 C mRNA and it’s protein expression levels in PAH group, PAH+HDAC4 i group and HDAC4 i group were increased at the 4 th week, and the difference of MEF2 C mRNA expression was statistically significant(P<0.05). Immunohistochemistry results showed OPN protein expression in mice pulmonary artery smooth muscle cells were increased in PAH group, PAH+HDAC4 i group and HDAC4 i group compared with NC gourp, while α-SMA and HDAC4 proteins expression were significantly decreased. Conclusion HDAC

关 键 词：组蛋白去乙酰化酶4 肌细胞增强因子2C 肺动脉高压 肺血管平滑肌 

分 类 号：R544.1[医药卫生—心血管疾病]