High Mobility Group Protein B1 Mediates the Role of the Neutrophil Extracellular Traps in the Progression of Acute Myocardial Infarction

  • Cardiovasc Drugs Ther. 2026 Jan 24. doi: 10.1007/s10557-026-07836-z.
Jing He  #  1 ,  Landi Wang  #  2 ,  Chen Xu  #  3 ,  Jingyi Liu  2 ,  Yuchao Wang  4 ,  Jing Han  2 ,  Jianhong Zhang  5 ,  Dayong Li  6 ,  Huanming Li  7 ,  Yong Liu  8 ,  Xuan Liu  9
Affiliations
  • 1. Department of Cardiology, Tianjin Fourth Central Hospital, No.3, Zhongshan Road, Hebei District, Tianjin, 300140, China.
  • 2. School of Medicine, Tianjin University, Tianjin, China.
  • 3. Department of Clinical Laboratory, Tianjin Fourth Central Hospital, Tianjin, China.
  • 4. Graduate School of Tianjin Medical University, Tianjin, China.
  • 5. Pharmacy Department, Tianjin Fourth Central Hospital, No.3, Zhongshan Road, Hebei District, Tianjin, China.
  • 6. General surgery department, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Institute of Endocrinology, Chu Hsien-I Memorial Hospital, Tianjin Medical University, Tianjin, China.
  • 7. Department of Cardiology, Tianjin Fourth Central Hospital, No.3, Zhongshan Road, Hebei District, Tianjin, 300140, China. [email protected].
  • 8. Department of Cardiology, Tianjin Fourth Central Hospital, No.3, Zhongshan Road, Hebei District, Tianjin, 300140, China. [email protected].
  • 9. Pharmacy Department, Tianjin Fourth Central Hospital, No.3, Zhongshan Road, Hebei District, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 41579229 DOI: 10.1007/s10557-026-07836-z
Abstract

Background: Neutrophil extracellular traps (NETs) play a crucial role in the pathogenesis of acute myocardial infarction (AMI), but the role of high-mobility group box 1 (HMGB1), a key target of the cell migration family, remains unclear.

Methods: This study investigated the HMGB1-CXCR4/CXCL12 -NETs pathway in ST-segment elevation myocardial infarction (STEMI) patients and a murine myocardial infarction (MI) model, with a focus on mechanisms associated with injury and aging.

Results: Peripheral blood analysis in 29 STEMI patients revealed elevated HMGB1 and myeloperoxidase (MPO) levels compared to controls. In C57BL/6J mice subjected to permanent left anterior descending (LAD) ligation, the CXCR4/CXCL12 axis was significantly upregulated in infarcted hearts, correlating with impaired ventricular function. Deoxyribonuclease (DNase) I or glycyrrhizic acid (a HMGB1 inhibitor) attenuated NETs formation and CXCR4/CXCL12 activation. Histological, echocardiographic, and transcriptomic analyses revealed that HMGB1 promotes NETs formation, exacerbating cardiac inflammation and fibrosis. Flow cytometry of murine blood demonstrated altered CD62L/CD11b expression, suggesting age-like immunophenotypic shifts in post-MI inflammation.

Conclusion: These findings delineate a pivotal HMGB1-CXCR4/CXCL12-NETs axis in AMI pathology, driving cardiac injury through inflammation and fibrosis, with implications for cellular aging/senescence. Targeting this pathway presents a promising therapeutic strategy for mitigating ischemia-related damage.

Keywords
Acute myocardial infarction; High-mobility group box 1; Neutrophil extracellular traps; “aged” neutrophils.
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