Atherosclerotic cardiovascular disease, particularly acute coronary syndrome (ACS), remains one of the leading causes of mortality worldwide. ACS can be triggered by plaque rupture or plaque erosion, the latter increasingly recognized as a mechanism distinct from macrophage-driven processes, primarily involving neutrophil activation. Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor characterized by somatic mutations in hematopoietic cells. Among CHIP-related mutations, JAK2 V617F has garnered attention due to its association with myeloproliferative neoplasms and increased thrombotic risk. However, its specific role in human plaque erosion and rupture has not been fully explored.
The research team from the Department of Cardiology at the Second Affiliated Hospital of Harbin Medical University, published in European Heart Journal, aimed to investigate the association of JAK2 V617F mutation with human plaque erosion and rupture risk, elucidating its role and potential mechanisms in ACS pathophysiology.
Figure 1. JAK2 V617F is associated with high-risk erosion, potentially due to enhanced neutrophil activity
First, the study analyzed 431 ST-segment elevation myocardial infarction (STEMI) patients who underwent optical coherence tomography (OCT) between August 2010 and September 2012, comparing 728 erosion patients, 919 rupture patients, and 804 controls without a history of myocardial infarction. Using digital droplet PCR to detect JAK2 V617F mutation frequency, it was found that 3.57% of erosion patients carried mutations with a variant allele frequency (VAF) ≥1%, indicating significant enrichment of JAK2 V617F mutations in erosion patients.
Figure 2. Prevalence of JAK2 V617F at different variant allele frequency levels in erosion, rupture, control, and GESUS cohorts
Next, the researchers further validated the association of JAK2 V617F mutation with plaque erosion through logistic regression analysis. At VAF ≥1%, JAK2 V617F showed a significant association with erosion but not with rupture. Moreover, mutations with VAF ≥2% were associated with extremely high risk in erosion patients, suggesting that high VAF mutations may be a key driver of erosion.
Figure 3. Forest plot and table of the association between JAK2 V617F and erosion or rupture
Finally, single-cell RNA sequencing was used to analyze the gene expression profile of neutrophils in JAK2 V617F mutation carriers, revealing significant upregulation of genes related to activation, adhesion, and migration (e.g., CD44, CD177, MMP-9). Quantitative PCR and flow cytometry further confirmed the high expression of these genes (e.g., CD177, CD44, TLR4) in JAK2 V617F mutation carriers, indicating that neutrophil activation may be a key mechanism by which JAK2 V617F contributes to plaque erosion.
Figure 4. Single-cell RNA sequencing analysis
This study is the first to systematically explore the role of JAK2 V617F mutation in human coronary plaque erosion and rupture, finding a significant association with erosion risk (over 10-fold), providing a basis for precise stratification of CHIP-related cardiovascular risk. By combining high-sensitivity ddPCR and single-cell RNA sequencing, the study accurately quantified mutation frequency and revealed changes in neutrophil function, with rigorous and complementary methods. It elucidated the mechanism by which JAK2 V617F promotes plaque erosion through enhanced neutrophil activation and NETosis, laying a theoretical foundation for targeted JAK2 therapeutic strategies.
JAK2 (Janus kinase 2) is a key molecule in the JAK-STAT signaling pathway, regulating cell proliferation, differentiation, and inflammatory responses. The JAK2 V617F mutation, through persistent activation of this pathway, leads to abnormal hematopoietic cell proliferation and enhanced inflammatory responses, closely linked to myeloproliferative neoplasms (MPN) and cardiovascular diseases. Beyond its role in MPN, JAK2 V617F is increasingly recognized in atherosclerosis research. Studies suggest that JAK2 V617F may exacerbate atherosclerosis by promoting neutrophil activation and NET formation. Another study found that JAK2 inhibitors can slow atherosclerosis progression in animal models, indicating potential therapeutic value.
Figure 5. Activation and negative regulation of the JAK/STAT signaling pathway
| Type |
Catalog No. |
Product Name |
| Protein |
HT091012 |
Recombinant Human JAK2 Protein, N-His |
| HB829012 |
Recombinant Human JAK1 Protein, N-His |
| HW525012 |
Recombinant Human JAK3 Protein, N-His |
| HB829022 |
Recombinant Human JAK1 Protein, C-His |
| Antibody |
HT091014 |
Anti-JAK2 Polyclonal Antibody |
| HB829014 |
Anti-JAK1 Polyclonal Antibody |
| HW525014 |
Anti-JAK3 Polyclonal Antibody |
