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Published on: January 22, 2017
SLC7A11-mediated cystine accumulation and Rac1-WRC-Arp2/3-driven actin cytoskeletal folding synergistically induce
Dongpu Shao1,2, Dongmei Chen1, Wenli Ma2
1Department of Cardiology, The First Hospital of Jilin University, Changchun, China.
Abstract:
Disulfidptosis, a newly identified form of cell death, holds significant biological relevance; however, its role in cardiovascular diseases remains poorly characterized. To investigate this, disulfide bond formation was evaluated using non-reducing Western blot, while cytoskeletal alterations were assessed via phalloidin staining. In vivo experiments using a rat model of myocardial infarction (MI) and in vitro experiments using H9c2 cardiomyocytes subjected to oxygen‑glucose deprivation (OGD) both demonstrated upregulation of SLC7A11, NADPH depletion, and cystine accumulation under OGD or MI conditions. Notably, increased disulfide bonds in actin cytoskeletal proteins were observed, leading to cytoskeletal collapse. Inhibition of SLC7A11 rescued disulfidptosis across all models. Cellular knockdown of Nckap1 (a core component of the Rac1-WRC-Arp2/3 pathway) suppressed disulfidptosis, whereas overexpression of Rac1, Nckap1, or Wave2 promoted it. Spatial transcriptomic analysis of human infarcted myocardium further validated the concurrent upregulation of SLC7A11 and Rac1-WRC-Arp2/3 pathway components. Collectively, these findings indicate that MI induces disulfidptosis-a novel cell death modality mediated by activation of the SLC7A11 and Rac1-WRC-Arp2/3 signaling pathways.
Insights
Myocardial infarction triggers disulfidptosis, a novel cell death pathway involving SLC7A11 and Rac1-WRC-Arp2/3 signaling. This process leads to cytoskeletal collapse and can be inhibited by targeting SLC7A11.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Molecular Pathology
Background:
- Disulfidptosis is a newly identified cell death form with poorly understood roles in cardiovascular diseases.
- Myocardial infarction (MI) is a major cardiovascular event with complex cellular pathology.
Purpose of the Study:
- To investigate the role and mechanism of disulfidptosis in myocardial infarction.
- To elucidate the signaling pathways involved in MI-induced cell death.
Main Methods:
- Non-reducing Western blot for disulfide bond analysis.
- Phalloidin staining for cytoskeletal assessment.
- In vivo rat MI model and in vitro H9c2 cell OGD model.
- SLC7A11 inhibition, gene knockdown/overexpression (Nckap1, Rac1, Wave2).
- Spatial transcriptomics of human infarcted myocardium.
Main Results:
- MI/OGD conditions upregulated SLC7A11, depleted NADPH, and accumulated cystine.
- Increased disulfide bonds in actin proteins caused cytoskeletal collapse, characteristic of disulfidptosis.
- SLC7A11 inhibition and Nckap1 knockdown suppressed disulfidptosis.
- Overexpression of Rac1, Nckap1, or Wave2 promoted disulfidptosis.
- Human infarcted myocardium showed co-upregulation of SLC7A11 and Rac1-WRC-Arp2/3 pathway components.
Conclusions:
- Myocardial infarction induces disulfidptosis via the SLC7A11 and Rac1-WRC-Arp2/3 signaling pathways.
- Disulfidptosis is a novel cell death modality implicated in cardiovascular disease pathogenesis.
- Targeting SLC7A11 presents a potential therapeutic strategy for MI.
