Related Experiment Video
Updated: Jun 8, 2025
Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
Persistent Ferroptosis Modulates Cardiac Remodeling and M2 Macrophage Polarization, Which Can be Mitigated by
Cheng Shen1, Yanian Wei1, Wen Kang1
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Abstract:
The role of ferroptosis, an iron-dependent lipid peroxidation regulated cell death pathway, remains obscure during myocardial infarction (MI) recovery. Our study aims to clarify ferroptosis' function in post-MI cardiac recovery, explore the consequences of iron overload and ferroptosis for myocardial remodeling, and assess the effects of Liproxstatin-1 (Lipro-1) treatment on macrophage functionality. Moreover, we examine the potential of Astaxanthin (ASTX), recognized for its antioxidative properties, to mitigate ferroptosis during MI recovery and its subsequent ramifications for myocardial remodeling. Our results demonstrate persistent ferroptosis during MI recovery, marked by decreased Glutathione Peroxidase 4 and increased Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) and Ferroportin 1 alongside elevated lipid peroxidation and iron levels up to D21. We identified a significant correlation between ferroptosis and macrophage activity, noted by the increase in macrophage populations co-expressing GPX4 and ACSL4 markers in the peri-infarct area by D21. Liproxstatin-1 treatment reduced macrophage (CD68 +) counts, promoted M2 polarization decreased inflammation, and improved cardiac function. Myocardial remodeling was improved in Lipro-1-treated rats, as shown by decreased fibrosis and reduced levels of α-SMA, Collagen I, and Collagen III proteins. ASTX treatment also exhibited an inhibiting effect on ferroptosis indicators, and encouraged M2 macrophage polarization, reduced inflammation, and enhanced both cardiac function and myocardial remodeling, mirroring the beneficial effects observed with Lipro-1. In summary, the interactions between ferroptosis, macrophage polarization, and myocardial remodeling are crucial for cardiac function improvement post-MI. Lipro-1 and ASTX emerge as promising therapeutic agents by modulating post-MI ferroptosis and related immune responses.
Insights
Ferroptosis, an iron-dependent cell death, persists post-myocardial infarction (MI), impacting cardiac recovery. Treatments like Liproxstatin-1 and Astaxanthin mitigate ferroptosis, improve macrophage function, and enhance heart repair.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Immunology
Background:
- Ferroptosis, a regulated cell death pathway, plays an underappreciated role in myocardial infarction (MI) recovery.
- Iron overload and ferroptosis can negatively influence cardiac remodeling after MI.
- Macrophage functionality is intricately linked to ferroptosis and cardiac healing processes.
Purpose of the Study:
- To elucidate the role of ferroptosis in post-MI cardiac recovery.
- To investigate the impact of iron overload and ferroptosis on myocardial remodeling.
- To evaluate the therapeutic potential of Liproxstatin-1 (Lipro-1) and Astaxanthin (ASTX) in modulating ferroptosis and improving cardiac outcomes.
Main Methods:
- Quantification of ferroptosis markers (GPX4, ACSL4, Ferroportin 1), lipid peroxidation, and iron levels up to 21 days post-MI.
- Assessment of macrophage populations (CD68+) and polarization (M1/M2) in the peri-infarct area.
- Evaluation of cardiac function, fibrosis, and expression of remodeling proteins (α-SMA, Collagen I, Collagen III) following Lipro-1 and ASTX treatments.
Main Results:
- Persistent ferroptosis markers, elevated lipid peroxidation, and iron accumulation were observed during MI recovery.
- A significant correlation was found between ferroptosis and increased macrophage populations expressing GPX4 and ACSL4.
- Both Lipro-1 and ASTX treatments reduced ferroptosis, decreased macrophage infiltration, promoted M2 polarization, reduced inflammation, improved cardiac function, and attenuated myocardial remodeling.
Conclusions:
- Ferroptosis, macrophage polarization, and myocardial remodeling are key interconnected processes influencing post-MI cardiac recovery.
- Lipro-1 and ASTX demonstrate therapeutic potential by targeting ferroptosis and modulating immune responses for improved cardiac healing.
