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Updated: Jun 29, 2025
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Antiferroptosis therapy alleviated the development of atherosclerosis
Zhou Yang1,2,3,4, Yue He5,6,7, Dejun Wu8
1Department of Vascular Surgery Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai China.
Insights
Ferroptosis, a cell death process, is linked to atherosclerosis (AS). Oxidized LDL induces ferroptosis by inhibiting GPX4, driving AS progression. Inhibiting ferroptosis shows promise for treating AS and its related conditions.
Area of Science:
- Biomedical research
- Cardiovascular pathology
- Cellular biology
Background:
- Ferroptosis is implicated in various diseases, but its role in atherosclerosis (AS) pathogenesis is not fully understood.
- Atherosclerosis involves complex pathological stages including endothelial cell injury, monocyte adhesion, and foam cell formation.
- Oxidized low-density lipoprotein (ox-LDL) is a critical factor in AS development.
Purpose of the Study:
- To elucidate the role of ferroptosis in the key pathological stages of atherosclerosis.
- To investigate the mechanism by which ox-LDL induces ferroptosis in endothelial cells.
- To evaluate the therapeutic potential of inhibiting ferroptosis in AS models.
Main Methods:
- Investigated ferroptosis in endothelial cells, monocyte adhesion, and foam cell formation.
- Assessed the effect of ox-LDL on ferroptosis and glutathione peroxidase 4 (GPX4) activity.
- Utilized a high-fat diet-induced mouse model of atherosclerosis.
- Administered ferroptosis inhibitors in vivo to evaluate therapeutic effects.
Main Results:
- Ox-LDL was confirmed to strongly induce ferroptosis in endothelial cells by inhibiting GPX4 activity.
- Inhibition of ferroptosis reduced monocyte adhesion and endothelial cell inflammation.
- Ferroptosis was found to regulate cholesterol efflux in macrophages, impacting foam cell formation.
- In vivo studies showed that high-fat diet induced ferroptosis, hyperlipidemia, and AS lesions, which were ameliorated by ferroptosis inhibitors.
Conclusions:
- Oxidized low-density lipoprotein induces ferroptosis by suppressing GPX4 activity, contributing to atherosclerosis progression.
- Inhibition of ferroptosis demonstrates significant therapeutic potential for atherosclerosis in vivo.
- Ferroptosis-associated biomarkers show promise for the diagnosis of atherosclerosis.
Abstract:
Ferroptosis has been confirmed to be associated with various diseases, but the relationship between ferroptosis and atherosclerosis (AS) remains unclear. Our research detailly clarified the roles of ferroptosis in three continuous and main pathological stages of AS respectively (injury of endothelial cells [ECs], adhesion of monocytes, and formation of foam cells). We confirmed that oxidized low-density lipoprotein (ox-LDL), the key factor in the pathogenesis of AS, strongly induced ferroptosis in ECs. Inhibition of ferroptosis repressed the adhesion of monocytes to ECs by inhibiting inflammation of ECs. Ferroptosis also participated in the formation of foam cells and lipids by regulating the cholesterol efflux of macrophages. Further research confirmed that ox-LDL repressedthe activity of glutathione peroxidase 4 (GPX4), the classic lipid peroxide scavenger. Treatment of a high-fat diet significantly induced ferroptosis in murine aortas and aortic sinuses, which was accompanied by AS lesions and hyperlipidemia. Treatment with ferroptosis inhibitors significantly reduced ferroptosis, hyperlipidemia, and AS lesion development. In conclusion, our research determined that ox-LDL induced ferroptosis by repressing the activity of GPX4. Antiferroptosis treatment showed promising treatment effects in vivo. Ferroptosis-associated indexes also showed promising diagnostic potential in AS patients.
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