Neutrophil Extracellular Traps-Mediated Intraplaque Angiogenesis and Microvascular Permeability Promote Rapid Plaque Progression following Myocardial Infarction.
4 affiliations
- 1Department of Cardiology, Shanghai Tenth People's Hospital , Tongji University School of Medicine, Shanghai, China.
- 2Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
- 3Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- 4Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Abstract
Despite adherence to guideline-recommended therapies, survivors of myocardial infarction (MI) remain at high risk for recurrent ischemic events. This study aimed to elucidate the underlying mechanisms responsible for this residual risk. Using Mendelian randomization analysis and retrospective cohort study, we established a causal relationship between MI and plaque progression, potentially mediated by neutrophils. In a murine atherosclerotic model, MI precipitated a marked expansion in plaque volume accompanied by reduced stability; these pathological changes are consistent with the hallmark features of rapid plaque progression, which may trigger recurrent ischemic events. Pharmacological inhibition and adoptive transfer experiments using Padi4flox/floxLyz2Cre mice confirmed the pivotal role of neutrophils in MI-driven rapid plaque progression via neutrophil extracellular traps (NETs) formation. Further investigations revealed that NETs promote intraplaque hemorrhage by facilitating intraplaque angiogenesis and enhancing microvascular permeability, thereby exacerbating post-MI atherosclerotic inflammation. Mechanistically, bioinformatics analyses and in vitro experiments identified the transcription factor ETS proto-oncogene 1 as a critical regulator of NETs-mediated angiogenesis and endothelial permeability through the activation of the vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 signaling pathway. In vivo pharmacological inhibition of ETS proto-oncogene 1 with TK216 markedly attenuated the rapid plaque progression after MI. In summary, this study provides the first comprehensive evidence that neutrophils and NETs drive rapid plaque progression following MI by modulating intraplaque angiogenesis and hemorrhage. These findings offer novel insights into the mechanisms underlying post-MI ischemic event recurrence and highlight promising therapeutic targets for clinical prevention.
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BibTeX
@article{lei2026neutrophil,
title = {{Neutrophil Extracellular Traps-Mediated Intraplaque Angiogenesis and Microvascular Permeability Promote Rapid Plaque Progression following Myocardial Infarction.}},
author = {Zhijun Lei and Yunfei Yin and Long Zeng and Na Yang and Ming Zhai and Yanxi Zeng and Yefei Shi and Qing Yu and Shiyu Gong and Weixia Jian and Jianhui Zhuang and Li Zhang and Wenhui Peng},
journal = {Research (Washington, D.C.)},
year = {2026},
month = oct,
doi = {10.34133/research.1451},
url = {https://europepmc.org/article/MED/42898474},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neutrophil Extracellular Traps-Mediated Intraplaque Angiogenesis and Microvascular Permeability Promote Rapid Plaque Progression following Myocardial Infarction.
AU - Zhijun Lei
AU - Yunfei Yin
AU - Long Zeng
AU - Na Yang
AU - Ming Zhai
AU - Yanxi Zeng
AU - Yefei Shi
AU - Qing Yu
AU - Shiyu Gong
AU - Weixia Jian
AU - Jianhui Zhuang
AU - Li Zhang
AU - Wenhui Peng
PY - 2026
DA - 2026/10/19
JO - Research (Washington, D.C.)
DO - 10.34133/research.1451
UR - https://europepmc.org/article/MED/42898474
AB - Despite adherence to guideline-recommended therapies, survivors of myocardial infarction (MI) remain at high risk for recurrent ischemic events. This study aimed to elucidate the underlying mechanisms responsible for this residual risk. Using Mendelian randomization analysis and retrospective cohort study, we established a causal relationship between MI and plaque progression, potentially mediated by neutrophils. In a murine atherosclerotic model, MI precipitated a marked expansion in plaque volume accompanied by reduced stability; these pathological changes are consistent with the hallmark features of rapid plaque progression, which may trigger recurrent ischemic events. Pharmacological inhibition and adoptive transfer experiments using Padi4flox/floxLyz2Cre mice confirmed the pivotal role of neutrophils in MI-driven rapid plaque progression via neutrophil extracellular traps (NETs) formation. Further investigations revealed that NETs promote intraplaque hemorrhage by facilitating intraplaque angiogenesis and enhancing microvascular permeability, thereby exacerbating post-MI atherosclerotic inflammation. Mechanistically, bioinformatics analyses and in vitro experiments identified the transcription factor ETS proto-oncogene 1 as a critical regulator of NETs-mediated angiogenesis and endothelial permeability through the activation of the vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 signaling pathway. In vivo pharmacological inhibition of ETS proto-oncogene 1 with TK216 markedly attenuated the rapid plaque progression after MI. In summary, this study provides the first comprehensive evidence that neutrophils and NETs drive rapid plaque progression following MI by modulating intraplaque angiogenesis and hemorrhage. These findings offer novel insights into the mechanisms underlying post-MI ischemic event recurrence and highlight promising therapeutic targets for clinical prevention.
SN - 2639-5274
ER -