中药新药与临床药理2025，Vol.36Issue(12)：2024-2033,10.DOI:10.19378/j.issn.1003-9783.2025.12.002
暖心康抑制心肌组织DNA损伤改善小鼠心力衰竭的作用及机制
Effect and Mechanism of Nuanxinkang Ameliorates Heart Failure in Mice by Inhibiting Myocardial DNA Damage
摘要
Abstract
Objective To investigate the effect and mechanism of Nuanxinkang(NXK)on myocardial DNA damage in mice with heart failure,focusing on lysine acetyltransferase 2A(GCN5).Methods Sixty mice were randomly divided into six groups(n=10 per group):sham-operated group,model group,sacubitril/valsartan group(25 mg·kg-1),and low-(2.93 g·kg-1),medium-(5.85 g·kg-1),and high-dose(11.70 g·kg-1)NXK groups.A pressure overload-induced heart failure model was established by transverse aortic constriction(TAC).The treatment groups received their respective drugs by gavage,while the sham and model groups received an equal volume of saline(10 mL·kg-1),once daily for 6 weeks.Cardiac function was assessed by echocardiography,measuring left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular internal diameter at end-systole(LVIDs),and left ventricular internal diameter at end-diastole(LVIDd).Myocardial histopathology was observed by hematoxylin-eosin(HE)staining.Protein expression of γH2AX and 8-OHdG in myocardial tissue was detected by immunohistochemistry.Cardiomyocyte apoptosis was assessed by TUNEL staining.mRNA expression levels of PARP,53BP1,and GCN5 in myocardial tissue were measured by qRT-PCR.Protein expression levels of GCN5,BAX,and Bcl-2 were determined by Western Blot.Results Compared with the sham group,the model group showed significantly decreased LVEF and LVFS(P＜0.01),and significantly increased LVIDs and LVIDd(P＜0.01).Cardiomyocytes were significantly enlarged,irregular in shape,and disorganized.Positive staining for γH2AX and 8-OHdG in myocardial tissue was markedly enhanced,appearing as diffuse brownish-yellow granules or plaques;protein expression of γH2AX and 8-OHdG and mRNA expression of PARP and 53BP1 were significantly upregulated(P＜0.01).Both protein and mRNA expression levels of GCN5 in myocardial tissue were significantly increased(P＜0.01).The TUNEL-positive cell rate in myocardial tissue was significantly elevated(P＜0.01).The expression level of the anti-apoptotic protein Bcl-2 was significantly decreased(P＜0.05),while the expression level of the pro-apoptotic protein BAX was significantly increased(P＜0.05).Compared with the model group,the medium-and high-dose NXK groups showed significantly decreased LVIDd(P＜0.05,P＜0.01).All NXK treatment groups exhibited significantly improved LVEF and LVFS(P＜0.01),significantly reduced LVIDs(P＜0.05,P＜0.01),and improved cardiomyocyte morphology and arrangement.The intensity of positive staining for γH2AX and 8-OHdG in myocardial tissue was markedly weakened;protein expression of γH2AX and 8-OHdG and mRNA expression of PARP and 53BP1 were significantly downregulated(P＜0.01).Protein and mRNA expression levels of GCN5 in myocardial tissue were significantly reduced(P＜0.01).All NXK dose groups showed significantly increased Bcl-2 protein expression(P＜0.05,P＜0.01)and significantly decreased BAX protein expression(P＜0.05,P＜0.01)in myocardial tissue.Conclusion Nuanxinkang can improve cardiac function,alleviate pathological damage,and reduce cardiomyocyte apoptosis in mice with pressure overload-induced heart failure.Its mechanism of action may be related to the inhibition of GCN5 expression and the subsequent reduction of myocardial DNA damage.关键词
暖心康/心力衰竭/赖氨酸乙酰转移酶2A/DNA损伤/凋亡/小鼠Key words
Nuanxinkang/heart failure/lysine acetyltransferase 2A/DNA damage/apoptosis/mice分类
医药卫生引用本文复制引用
时恺芸,王陵军,梁碧容,吴辉,李志芳,方红城..暖心康抑制心肌组织DNA损伤改善小鼠心力衰竭的作用及机制[J].中药新药与临床药理,2025,36(12):2024-2033,10.基金项目
国家自然科学基金面上项目(82474403) （82474403）
广东省自然科学基金项目(2023A1515010282,2024A15150121712) （2023A1515010282,2024A15150121712）
国家中医药传承创新中心项目(2023QN19) （2023QN19）
深圳市可持续发展科技专项(JCYJ20230807141402005) （JCYJ20230807141402005）
深圳市"医疗卫生三名工程"项目(SZZYSM202106006). （SZZYSM202106006）
