SIRT1 Agonist Treatment of Mice with Coronary Artery Disease Improves Myocardial Function by modulating Nrf2-GPX4 Ferroptosis Pathway

Xiaoxia SHEN; Xiaodong ZHAO; Yongjian SONG

doi:10.12259/j.issn.2095-610X.S20250507

Volume 46 Issue 5

May 2025

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Xiaoxia SHEN, Xiaodong ZHAO, Yongjian SONG. SIRT1 Agonist Treatment of Mice with Coronary Artery Disease Improves Myocardial Function by modulating Nrf2-GPX4 Ferroptosis Pathway[J]. Journal of Kunming Medical University, 2025, 46(5): 55-64. doi: 10.12259/j.issn.2095-610X.S20250507

Citation:

Xiaoxia SHEN, Xiaodong ZHAO, Yongjian SONG. SIRT1 Agonist Treatment of Mice with Coronary Artery Disease Improves Myocardial Function by modulating Nrf2-GPX4 Ferroptosis Pathway[J]. Journal of Kunming Medical University, 2025, 46(5): 55-64. doi: 10.12259/j.issn.2095-610X.S20250507

Citation:

Xiaoxia SHEN, Xiaodong ZHAO, Yongjian SONG. SIRT1 Agonist Treatment of Mice with Coronary Artery Disease Improves Myocardial Function by modulating Nrf2-GPX4 Ferroptosis Pathway[J]. Journal of Kunming Medical University, 2025, 46(5): 55-64. doi: 10.12259/j.issn.2095-610X.S20250507

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SIRT1 Agonist Treatment of Mice with Coronary Artery Disease Improves Myocardial Function by modulating Nrf2-GPX4 Ferroptosis Pathway

doi: 10.12259/j.issn.2095-610X.S20250507

Department of Cardiology，The First Hospital of Zhangjiakou，Hebei Zhangjiakou 075000，China

Received Date: 2025-01-02
Publish Date: 2025-05-30

Abstract

Abstract

Objective The objective of this research was to examine the cardioprotective properties of a SIRT1 agonist in mice afflicted with coronary artery disease （CAD）. Methods Using the random number table method, 60 male C57BL/6J mice were randomly divided into a control group, a model group, an SRT1 agonist group （Group SRT 1460, 30 mg/kg）, an Nrf2 inhibitor group （ML385 group, 10 mg/kg）, and a combined treatment group of SRT 1460 + ML385, with 12 mice in each group. The control group mice were fed with normal feed, and the other groups of mice were fed with high-fat feed to create atherosclerosis mouse model. The modeling period was 12 weeks. After the successful construction of the model, ultrasonic parameters were used to detect the myocardial function of mice; two-dimensional ultrasound spot tracking technology was used to detect the strain of each layer of left ventricular myocardium. Pathological alterations in myocardial tissue were detected via HE staining, and the levels of cTnI, LDH and CK were measured using ELISA. Cardiomyocyte apoptosis was evaluated using TUNEL analysis, and levels of ROS in myocardial tissue were measured via DHE fluorescence assay. Additionally, SOD activity and MDA, GSH and Fe²⁺ contents in myocardial tissue were determined using colorimetry. Finally, gene and protein expressions of Nrf2, GPX4, FTH1, and ACSL4 were assessed through qRT-PCR and Western blot analysis. Results A significant decrease in LVEDd and LVPWd levels was observed in the SRT 1460 group （P < 0.05）, whereas increases in GLSendo, GLSmid, and GCSendo levels were identified. A decrease in collagen fiber deposition was observed in the SRT 1460 group, in which the myocardium space narrowed. In comparison to the control group, the SRT 1460 group showed reductions in serum cTnI, CK, and LDH levels, cardiomyocyte apoptosis rate, ROS, MDA, and Fe²⁺ contents, as well as ACSL4 mRNA and protein levels （P < 0.05）. An increase in SOD activity and GSH content as well as in Nrf2, GPX4, and FTH1 mRNA and protein levels was observed （P < 0.05）. By inhibiting the nuclear translocation of Nrf2, ML385 could significantly block the regulatory effect of SRT 1460 （P < 0.05）. Conclusion It has been shown that SRT 1460 enhances GLSendo, GLSmid, and GCSmid, and improves left ventricular remodeling and systolic function in mice with CAD, in part because it regulates the Nrf2-GPX4 ferroptosis pathway.
- Coronary artery disease,
- SIRT1 agonist,
- Ferroptosis,
- Myocardial function,
- Nuclear factor erythroid 2-related factor 2,
- Glutathione peroxidase 4

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References(28)

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