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The mechanism of Laggerae Herba in improving chronic heart failure by inhibiting ferroptosis through the Nrf2/SLC7A11/GPX4 signaling pathway

  • role： First author第一作者
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

  • Introduction：肖金陵，女，在读硕士生
XIAO Jinling1,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

HUANG Kai1,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

WEI Xiaoqi1,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

FAN Xinyi1,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

CHAI Wangjing1,  
  • Affiliation：

    Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

HAN Jing2,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

GAO Kuo1,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

YU Xue1,  
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

LI Fanghe1,  
  • role： Corresponding author通信作者
  • Affiliation：

    School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

  • Email：guoshz@bucm.edu.cn
  • Introduction：Prof. GUO Shuzhen, Ph.D., Doctoral Supervisor. School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, the Intersection of Yangguang South Street and Baiyang East Road, Fangshan District, Beijing 102488. E-mail: guoshz@bucm.edu.cn
GUO Shuzhen1*

추상적인

ObjectiveTo 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.MethodsTwenty-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.ResultsCompared 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.ConclusionLaggerae 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.

키워드

chronic heart failure;Laggerae Herba;pressure overload;ferroptosis;mice

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