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Targeting GPX4 alleviates ferroptosis and retards abdominal aortic aneurysm formation
Yu Shi1, Yi Zhao1, Si-Jia Sun1
1Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
Abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of glutathione peroxidase 4 (GPX4) itself determined ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments in vitro demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.
Insights
Ferroptosis, a cell death linked to lipid peroxidation, plays a key role in abdominal aortic aneurysm (AAA). Overexpressing glutathione peroxidase 4 (GPX4) inhibits ferroptosis, preventing AAA progression and inflammation.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Molecular Medicine
Background:
- Abdominal aortic aneurysm (AAA) is a dangerous cardiovascular condition linked to inflammation and vascular smooth muscle cell (VSMC) loss.
- Ferroptosis, an iron-dependent cell death, involves lipid peroxidation, but its specific role in AAA pathogenesis is unclear.
Purpose of the Study:
- To investigate the role of ferroptosis and glutathione peroxidase 4 (GPX4) in abdominal aortic aneurysm (AAA) development.
- To determine if targeting ferroptosis via GPX4 can prevent AAA progression.
Main Methods:
- Ferroptosis detection in human AAA tissues, mouse AAA models (elastase- and angiotensin II-induced), and cultured VSMCs.
- Genetic overexpression of GPX4 to inhibit ferroptosis in AAA models.
- Analysis of vascular remodeling, inflammatory responses, and macrophage/monocyte activity.
- In vitro studies on JAK1/STAT3 signaling and macrophage polarization.
Main Results:
- Ferroptosis was observed in human AAA, experimental mouse AAA, and Ang II-treated VSMCs.
- GPX4 overexpression significantly reduced vascular remodeling and inflammation in AAA models.
- GPX4 modulated macrophage migration and activation and inhibited IL-6-induced JAK1/STAT3 signaling in VSMCs.
Conclusions:
- Ferroptosis is a significant factor in AAA pathogenesis.
- Therapeutic strategies targeting GPX4 show promise for treating abdominal aortic aneurysms.
