THZ1缓解心肌肥大保护射血分数降低的心力衰竭小鼠心脏功能的机制研究  

Mechanism of THZ1 Alleviates Cardiac Hypertrophy and Protects the Heart Function of Heart Failure Mice with Reduced Ejection Fraction

作　　者：赵勇 陈佳显 张远生 ZHAO Yong;CHEN Jiaxian;ZHANG Yuansheng(The Second Affiliated Hospital of Hainan Medical University,Haikou 570203,Hainan,China)

机构地区：[1]海南医科大学第二附属医院,海口570203

出　　处：《中西医结合心脑血管病杂志》2025年第3期371-377,共7页Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease

基　　金：海南省卫生健康行业科研项目(No.21A200083)。

摘　　要：目的:探讨细胞周期蛋白依赖性激酶7(CDK7)抑制剂THZ1对射血分数降低的心力衰竭(HFrEF)小鼠心肌肥大和心脏功能的保护作用并探讨其作用机制。方法:将10周龄雄性C57BL/6小鼠成年应用永久性冠状动脉结扎术诱导HFrEF小鼠模型(HFrEF组,12只),12只小鼠接受假手术(sham组)。54只小鼠行冠状动脉结扎术,将存活的36只小鼠分为HFrEF组、THZ1组、THZ1+Colivelin TFA组,每组12只小鼠。THZ1组静脉注射THZ1,THZ1+Colivelin TFA组静脉注射THZ1与信号转导与转录激活因子3(STAT3)激活剂Colivelin TFA静脉注射。比较各组心重/胫骨长度比(HW/TL)、心肥大指数(HWI)、左室肥大指数(LVWI)、左室射血分数(LVEF)、左室短轴缩短率(LVFS)、左室前壁厚度(LVAWd)、左室后壁厚度(LVPWd)、左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、左室短轴缩短分数(LVFS)、左室舒张期容积(LVdVol)、左室收缩期容积(LVsVol)。实时荧光定量聚合酶链式反应(RT-q PCR)或大白免疫(Western Blot)检测各组小鼠心肌组织中CDK7、STAT3、Tyr705磷酸化的STAT3(p-STAT3)表达。结果:与sham组比较,HFrEF组HW/TL、HWI、LVWI、LVEF、LVFS、LVAWd、LVPWd、LVEDD、LVESD、LVFS、LVdVol、LVsVol均明显增加(P<0.05),且CDK7、STAT3、p-STAT3的表达均明显增加(P<0.05)。与HFrEF组比较,THZ1组HW/TL、HWI、LVWI、LVEF、LVFS、LVAWd、LVPWd、LVEDD、LVESD、LVdVol、LVsVol均明显降低(P<0.05),且CDK7、STAT3、p-STAT3表达均被抑制(P<0.05)。与THZ1组比较,THZ1+Colivelin TFA组HW/TL、HWI、LVWI、LVEF、LVFS、LVAWd、LVPWd、LVEDD、LVESD、LVdVol、LVsVol的指标均增加(P<0.05)。结论:CDK7抑制剂THZ1通过抑制STAT3缓解心肌肥大并改善HFrEF小鼠的心脏功能。Objective:To investigate the protective effect of cyclin-dependent kinase 7(CDK7)inhibitor THZ1 on myocardial hypertrophy and cardiac function in heart failure with reduced ejection fraction(HFrEF)mice and explore the mechanism.Methods:10-week-old male C57BL/6 mice were induced into HFrEF mouse model by permanent coronary artery ligation(HFrEF group,n=12)and 12 mice underwent sham surgery(sham group).Fifty-four mice underwent coronary artery ligation.Among them,36 surviving mice were divided into three groups:the HFrEF group,the THZ1 group,and the THZ1+Colivelin TFA group,with 12 mice in each group.The THZ1 group was intravenously injected with THZ1,and the THZ1+Colivelin TFA group was intravenously injected with THZ1 and the signal transduction and activator of transcription-3(STAT3)activator Colivelin TFA.The heart weight/tibia length ratio(HW/TL),heart weight index(HWI),left ventricle weight index(LVWI),left ventricular ejection fraction(LVEF),left ventricular fraction shortening(LVFS),left ventricular anterior wall thickness(LVAWd),left ventricular posterior wall thickness(LVPWd),left ventricular end-diastolic dimension(LVEDD),left ventricular endsystolic diameter(LVESD),fractional shortening(FS),left ventricular diastolic volume(LVdVol),left ventricular systolic volume(LVsVol)were compared among groups.Quantitative PCR(qPCR)or Western Blot were used to detect the expression of CDK7,STAT3,and Tyr705 phosphorylated STAT3(p-STAT3)in myocardial tissue.Results:Compared with the sham group,the indicators of HW/TL,HWI,LVWI,LVEF,LVFS,LVAWd,LVPWd,LVEDD,LVESD,FS,LVdVol,and LVsVol in the HFrEF group were significantly increased.The expressions of CDK7,STAT3,and p-STAT3 were significantly increased(all P<0.05).Compared with HFrEF group,the indexes of HW/TL,HWI,LVWI,LVEF,LVFS,LVAWd,LVPWd,LVEDD,LVESD,LVdVol,and LVsVol in THZ1 group were significantly decreased.The expressions of CDK7,STAT3,and p-STAT3 were inhibited(all P<0.05).Compared with THZ1 group,The indexes of HW/TL,HWI,LVWI,LVEF,LVFS,LVAWd,LVPWd,LVEDD,LVESD,FS,LVd

关 键 词：射血分数降低的心力衰竭 细胞周期蛋白依赖性激酶7抑制剂 THZ1 信号传导与转录激活子3 心肌肥大 心脏功能 实验研究 

分 类 号：R541.6[医药卫生—心血管疾病]