北京中医药大学学报2025，Vol.48Issue(3)：343-353,11.DOI:10.3969/j.issn.1006-2157.2025.03.008
臭灵丹草调控Nrf2/SLC7A11/GPX4信号通路抑制铁死亡改善慢性心力衰竭的机制研究
The mechanism of Laggerae Herba in improving chronic heart failure by inhibiting ferroptosis through the Nrf2/SLC7A11/GPX4 signaling pathway
摘要
Abstract
Objective To investigate the role and mechanism of the heat-clearing and detoxifying drug Laggerae Herba in regulating the nuclear factor-erythroid 2-related factor-2(Nrf2)/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4)signaling pathway to inhibit ferroptosis and improve chronic heart failure induced by transverse aortic arch constriction in mice.Methods Twenty-four male ICR mice were divided into the sham(n=6)and transverse aortic arch constriction groups(n=18)according to the random number table method.The transverse aortic arch constriction group underwent transverse aortic constriction surgery to establish models.After modeling,the transverse aortic arch constriction group was further divided into the model,captopril,and Laggerae Herba groups according to the random number table method,with six mice per group.The captopril(15 mg/kg)and Laggerae Herba groups(1.95 g/kg)received the corresponding drugs by gavage,whereas the sham operation and model groups were administered the same volume of ultrapure water by gavage once a day for four consecutive weeks.After treatment,the cardiac function indexes of mice in each group were detected using ultrasound.The heart mass and tibia length were measured to calculate the ratio of heart weight to tibia length.Hematoxylin and eosin staining were used to observe the pathological changes in myocardial tissue.Masson staining was used to observe the degree of myocardial fibrosis.Wheat germ agglutinin staining was used to observe the degree of myocardial cell hypertrophy.Prussian blue staining was used to observe the iron deposition in myocardial tissue.An enzyme-linked immunosorbent assay was used to detect the amino-terminal pro-brain natriuretic peptide(NT-proBNP)and glutathione(GSH)contents in mice serum.Colorimetry was used to detect the malondialdehyde(MDA)content in mice serum.Western blotting was used to detect the Nrf2,GPX4,SLC7A11,and ferritin heavy chain 1(FTH1)protein expressions in mice cardiac tissue.Results Compared with the sham group,in the model group,the ejection fraction(EF)and fractional shortening(FS)of mice decreased,the left ventricular end-systolic volume(LVESV)and left ventricular end-systolic diameter(LVESD)increased,the left ventricular anterior wall end-systolic thickness(LVAWs)and left ventricular posterior wall end-systolic thickness(LVPWs)decreased,the ratio of heart weight to tibia length increased,the myocardial tissue morphology changed,myocardial fibrosis increased,the cross-sectional area of myocardial cells increased,iron deposition appeared in myocardial tissue,the serum NT-proBNP and MDA levels increased,the GSH level decreased,and Nrf2,GPX4,SLC7A11,and FTH1 protein expressions in cardiac tissue decreased(P<0.05).Compared with the model group,in the captopril and Laggerae Herba groups,the EF,FS,and LVAWs increased,the LVESV and LVESD decreased,the ratio of heart weight to tibia length decreased,the myocardial cells were arranged neatly,the degree of myocardial fibrosis decreased,the cross-sectional area of myocardial cells decreased,the serum NT-proBNP level decreased,and the GSH level increased.Compared with the model group,the LVPWs increased,the iron deposition in myocardial tissue decreased,the serum MDA level decreased,and Nrf2,GPX4,SLC7A11,and FTH1 protein expressions in cardiac tissue increased(P<0.05)in the Laggerae Herba group.Conclusion Laggerae Herba improves the cardiac function of mice with chronic heart failure caused by transverse aortic arch constriction,reduces the pathological remodeling of the heart,and reduces fibrosis.Its mechanism may be related to Nrf2/SLC7A11/GPX4 pathway-mediated ferroptosis.关键词
慢性心力衰竭/臭灵丹草/压力超负荷/铁死亡/小鼠Key words
chronic heart failure/Laggerae Herba/pressure overload/ferroptosis/mice分类
医药卫生引用本文复制引用
肖金陵,郭淑贞,黄凯,魏小棋,范昕怡,柴王静,韩静,高阔,于雪,李芳赫..臭灵丹草调控Nrf2/SLC7A11/GPX4信号通路抑制铁死亡改善慢性心力衰竭的机制研究[J].北京中医药大学学报,2025,48(3):343-353,11.基金项目
国家自然科学基金项目(No.81922075,No.82174206) National Natural Science Foundation of China(Nos.81922075 and 82174206) （No.81922075,No.82174206）
