北京中医药大学学报2025，Vol.48Issue(4)：516-528,13.DOI:10.3969/j.issn.1006-2157.2025.04.009
心阳片对慢性心力衰竭小鼠心肌细胞铁死亡的作用及机制研究
Study on the effect and mechanism of Xinyang Tablet on myocardial ferroptosis in mice with chronic heart failure
摘要
Abstract
Objective Exploring the effect and mechanism of Xinyang Tablet on reduction of ferroptosis in myocardial cells from mice with chronic heart failure.Methods Sixty C57BL/6J mice were randomly assigned to the sham,model,Xinyang Tablet low-dose(0.34 g/kg),Xinyang Tablet medium-dose(0.68 g/kg),Xinyang Tablet high-dose(1.36 g/kg),and perindopril(0.607 mg/kg)groups using a random number table method(10 mice in each group).Except for the sham group,all other groups underwent aortic arch constriction surgery to construct a chronic heart failure model.On the third day after completion of the modeling,each treatment group was administered the corresponding medication by gavage,while the sham and model groups were administered equal volumes of water by gavage once a day for eight consecutive weeks.After treatment,cardiac ultrasound was used to detect the structure and function of the mouse heart.Hematoxylin and eosin staining was used to detect pathological changes in mouse heart tissue.Masson staining was used to detect the proportion of fibrotic area of mouse heart tissue.Realtime fluorescence PCR was used to detect the mRNA expression of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),collagen 3α(Col3α),and myosin heavy chain 7(MYH7)in mouse myocardial tissue.Transmission electron microscope was used to detect the ultrastructure of myocardial cell mitochondria.Reactive oxygen species(ROS)staining was used to detect the mean fluorescence intensity of ROS in myocardial tissue.Micro-determination was used to detect superoxide dismutase(SOD)activity in myocardial tissue.An immunofluorescence assay was used to detect the mean fluorescence intensity of phosphorylated histone deacetylase 2(p-HDAC2)in myocardial cell.Western blotting was used to detect the protein expression of nuclear factor-erythroid 2-related factor 2(Nrf2),p-HDAC2,nicotinamide adenine dinucleotide phosphate oxidase 1(NOX1),glutathione peroxidase 4(GPX4),and cystine glutamate reverse transporter(xCT)in mouse myocardial tissue.Results Compared to the sham group,the model group showed a decrease in left ventricular ejection fraction(LVEF),left ventricular fraction shortening(LVFS),an increase in left ventricular end-systolic diameter(LVESD)and left ventricular end-diastolic diameter(LVEDD),an increase in the proportion of cardiac fibrosis area,an increase in relative expression levels of ANP,BNP,Col3α,and MYH7 mRNA,an increase in ROS mean fluorescence intensity,a decrease in SOD activity,an increase in mean fluorescence intensity of p-HDAC2,an increase in relative expression levels of p-HDAC2 and NOX1 proteins,and a decrease in relative expression levels of Nrf2,GPX4,and xCT proteins(P<0.05).Myocardial fibrosis lesions are obvious,with disordered mitochondrial arrangement,decreased volume and shrinkage,increased membrane density,and reduced mitochondrial cristae.Compared to the model group,the LVEF and LVFS of mice in each dose group of Xinyang Tablet and the perindopril group increased,LVESD and LVEDD decreased,the proportion of fibrotic area of heart tissue decreased,the relative expression levels of ANP,BNP,Col3α,MYH7 mRNA decreased,ROS mean fluorescence intensity decreased,SOD activity increased,mean fluorescence intensity of p-HDAC2 decreased,relative expression levels of p-HDAC2 and NOX1 proteins decreased,and relative expression levels of Nrf2 and xCT proteins increased(P<0.05).Myocardial fibrosis was reduced,the mitochondrial arrangement was more regular,the mitochondria enlarged,the membrane density was reduced,and mitochondrial cristae increased.Compared to the model group,the relative expression level of the GPX4 protein in myocardial tissue increased in the Xinyang Tablet medium-,high-dose,and the perindopril groups(P<0.05).Conclusion Xinyang Tablet can improve ferroptosis and ventricular remodeling in mice with chronic heart failure by regulating the HDAC2-mediated Nrf2 antioxidant pathway.关键词
心阳片/慢性心力衰竭/铁死亡/组蛋白去乙酰化酶 2/核转录因子红系 2 相关因子 2 抗氧化通路/小鼠Key words
Xinyang Tablet/chronic heart failure/ferroptosis/histone deacetylase 2/nuclear factor-erythroid 2-related factor 2 antioxidant pathway/mice分类
医药卫生引用本文复制引用
康锦花,梁朋朋,周小雄,刘澳,杨忠奇,吴红彦..心阳片对慢性心力衰竭小鼠心肌细胞铁死亡的作用及机制研究[J].北京中医药大学学报,2025,48(4):516-528,13.基金项目
国家自然科学基金面上项目(No.82174316) （No.82174316）
广州市科技局基础与应用基础研究项目(No.2024A04J4491) （No.2024A04J4491）
深圳市"医疗卫生三名工程"项目(No.SZZYSM202201007) （No.SZZYSM202201007）
广州市科技局市校(院)企联合资助项目(No.2023A03J0288) National Natural Science Foundation of China(No.82174316) （院）
