Mechanism of THZ1 Alleviates Cardiac Hypertrophy and Protects the Heart Function of Heart Failure Mice with Reduced Ejection Fraction
ZHAO Yong
CHEN Jiaxian
ZHANG Yuansheng
Abstract：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 end-systolic 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,LVdVol,and LVsVol in THZ1+Colivelin TFA group were increased(all P＜0.05).Conclusion:CDK7 inhibitor THZ1 alleviates cardiac hypertrophy and improves cardiac function in HFrEF mice by inhibiting STAT3.
Keywords：heart failure with reduced ejection fractioncyclin dependent kinase 7THZ1activator of signaling and transcription 3myocardial hypertrophyheart functionexperimental study
Publication Date：2025-02-15
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：7( 371-377 )