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Astragaloside IV mitigates myocardial ischemia/reperfusion injury by modulating the 14-3-3η/GPX4 axis, reducing
Rui-Yuan Zeng1, Zhi-Cong Qiu1, Shi-Tao Zhao1
1Department of Cardiovascular Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China; Institute of Cardiovascular Surgical Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China.
Background:
Acute myocardial infarction (AMI) requires timely restoration of cardiac perfusion, which often leads to myocardial ischemia/reperfusion injury (MIRI). Ferroptosis, apoptosis, and mitochondrial dysfunction play critical roles in this process. Astragaloside IV (Ast) has been demonstrated to possess multiple biological functions, yet its protective mechanisms against MIRI remain unclear.
Objective:
The aim of this study was to investigate the protective effects of Ast against MIRI and its underlying mechanisms.
Methods:
This study utilized H9c2 cell anoxia/reoxygenation (A/R) and Sprague-Dawley (SD) rat MIRI models to evaluate Ast's protective effects. Cardiac injury was assessed by echocardiography, HE staining, and TTC staining; superoxide levels by DHE staining; apoptosis by TUNEL staining; and protein expression by Western blotting. Ferroptosis-, apoptosis-, and mitochondrial function-related indicators were detected using commercial kits, and mitochondrial ultrastructure by TEM. The expression, localization, and interaction of 14-3-3η and GPX4 were investigated by confocal microscopy and Co-IP.
Results:
Ast pretreatment significantly attenuated the decline in LVEF and LVFS, reduced myocardial infarct size, decreased ROS and ferrous iron accumulation, alleviated alterations in ferroptosis markers (GPX4, PTGS2) and lipid peroxidation indicators (MDA, 4-HNE), increased the Bcl-2/Bax ratio, and maintained mitochondrial function parameters (NDUFB8, UQCRC2, MMP) following MIRI. Additionally, Ast pretreatment upregulated 14-3-3η expression and enhanced its interaction with GPX4, with 14-3-3η regulating GPX4 stability through modulating its ubiquitination.
Conclusion:
This study demonstrates that Ast ameliorates ferroptosis, apoptosis, and mitochondrial dysfunction in MIRI by modulating the 14-3-3η/GPX4 axis, thereby protecting myocardial tissue.
Insights
Astragaloside IV protects against myocardial ischemia/reperfusion injury (MIRI) by reducing ferroptosis, apoptosis, and mitochondrial dysfunction. It modulates the 14-3-3η/GPX4 axis, preserving cardiac tissue function.
Area of Science:
- Cardiology
- Biochemistry
- Cell Biology
Background:
- Myocardial ischemia/reperfusion injury (MIRI) is a significant complication of acute myocardial infarction (AMI).
- Ferroptosis, apoptosis, and mitochondrial dysfunction are key pathological processes in MIRI.
- The protective mechanisms of Astragaloside IV (Ast) against MIRI are not fully understood.
Purpose of the Study:
- To investigate the protective effects of Astragaloside IV (Ast) against myocardial ischemia/reperfusion injury (MIRI).
- To elucidate the underlying molecular mechanisms of Ast's cardioprotective action in MIRI.
Main Methods:
- Utilized H9c2 cell anoxia/reoxygenation and Sprague-Dawley rat MIRI models.
- Assessed cardiac injury, oxidative stress, apoptosis, ferroptosis, and mitochondrial function using various assays.
- Investigated the expression, localization, and interaction of 14-3-3η and GPX4 via Western blotting, confocal microscopy, and Co-IP.
Main Results:
- Ast pretreatment significantly improved cardiac function and reduced infarct size in MIRI models.
- Ast attenuated ferroptosis, apoptosis, and oxidative stress, while preserving mitochondrial function.
- Ast upregulated 14-3-3η, enhancing its interaction with GPX4 and stabilizing GPX4 through modulating ubiquitination.
Conclusions:
- Astragaloside IV ameliorates MIRI by mitigating ferroptosis, apoptosis, and mitochondrial dysfunction.
- The protective effects of Ast are mediated through the modulation of the 14-3-3η/GPX4 axis.
- Ast demonstrates significant cardioprotective potential against myocardial ischemia/reperfusion injury.
