IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI
Abstract
1. Introduction
2. Results
2.1. Baseline Characteristics
2.2. Investigations in Coronary Thrombi
2.2.1. Associations Between PAD4, IL-6R, and IL-6 mRNA Levels
2.2.2. Associations Between PAD4 mRNA Levels and Troponin T
2.2.3. Immunofluorescence Investigations of NETosis
2.3. Investigations in Peripheral Blood
2.3.1. Associations Between PAD4 mRNA, IL-6, IL-6R, and NETs
2.3.2. Comparison of Coronary PAD4 mRNA and Circulating Markers
3. Discussion
Limitations
4. Materials and Methods
4.1. Study Design
4.2. Thrombi Preparation
4.3. Blood Sampling Protocol
4.4. Laboratory Analysis
4.5. Statistical Methods
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
STEMI | ST-elevation myocardial infarction |
Il-6 | Interleukin-6 |
IL-6R | Interleukin-6 receptor |
NETs | Neutrophil extracellular traps |
PAD4 | Peptidylarginine deiminase 4 |
dsDNA | Double-stranded deoxyribonucleic acid |
H3Cit | Citrullinated histone H3 |
MPO-DNA | Myeloperioxidase bound to deoxyribonucleic acid |
NLRP3 | NOD-, LRR-, and pyrin domain-containing protein 3 |
ASSAIL-MI | Assessing the effect of anti-IL-6 treatment in myocardial infarction |
PCI | Percutaneous coronary intervention |
FFPE | Formalin-fixed, paraffin-embedded |
ELISA | Enzyme-linked immunosorbent assay |
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Total n = 33 | |
---|---|
Age, years | 60 (±11) |
Females | 3 (9%) |
Current or previous smoker | 27 (84%) |
BMI, kg/m2 | 27.7 (23.4, 28.6) |
sBP, mmHg | 127 (±31) |
dBP, mmHg | 82 (±19) |
Heart rate | 70 (65, 90) |
Prior myocardial infarction | 1 (3%) |
Prior hypertension | 11 (33%) |
Prior diabetes mellitus type 2 | 4 (12%) |
Prior medication: | |
Acetylsalicylic acid | 6 (18%) |
P2Y12-inhibitor | 2 (6%) |
Anticoagulation | 3 (9%) |
RAAS inhibitors | 5 (15%) |
Betablocker | 4 (12%) |
Aldosterone antagonist | 0 (0%) |
Statins | 6 (18%) |
Symptom start to PCI, min | 152 (122, 343) |
Culprit artery: | |
LAD | 16 (48%) |
Cx | 6 (18%) |
RCA | 11 (33%) |
Troponin T peak, µg/L | 3434 (1250, 6967) |
CRP, mg/L | 2.71 (0.96, 6.03) |
Gene Expression in Thrombi | Gene Expression in Circulating Leukocytes | Circulating Levels | |
---|---|---|---|
IL-6 | √ | √ | √ |
IL-6R | √ | √ | √ |
PAD4 | √ | √ | √ |
dsDNA | x | x | √ |
MPO-DNA | x | x | √ |
H3Cit | x | x | √ |
Univariate | Multivariate | |||||
---|---|---|---|---|---|---|
β | CI | p-value | β | CI | p-value | |
Association with PAD4 mRNA in coronary thrombi | ||||||
IL-6R mRNA | 0.34 | 0.16–0.51 | 0.001 | 0.34 | 0.16–0.53 | 0.001 * |
Circulating peak troponin T, quartile q4 vs. 1–3 | 1.0 | 0.20–1.80 | 0.016 | 1.15 | 0.27–2.04 | 0.013 * |
Association with PAD4 mRNA in circulating leukocytes | ||||||
IL-6R mRNA | 0.98 | 0.18–1.77 | 0.017 | 0.92 | 0.07–1.77 | 0.036 * |
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Kindberg, K.M.; Nordeng, J.; Langseth, M.S.; Schandiz, H.; Roald, B.; Solheim, S.; Seljeflot, I.; Stokke, M.K.; Helseth, R. IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI. Int. J. Mol. Sci. 2025, 26, 5348. https://doi.org/10.3390/ijms26115348
Kindberg KM, Nordeng J, Langseth MS, Schandiz H, Roald B, Solheim S, Seljeflot I, Stokke MK, Helseth R. IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI. International Journal of Molecular Sciences. 2025; 26(11):5348. https://doi.org/10.3390/ijms26115348
Chicago/Turabian StyleKindberg, Kristine Mørk, Jostein Nordeng, Miriam Sjåstad Langseth, Hossein Schandiz, Borghild Roald, Svein Solheim, Ingebjørg Seljeflot, Mathis Korseberg Stokke, and Ragnhild Helseth. 2025. "IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI" International Journal of Molecular Sciences 26, no. 11: 5348. https://doi.org/10.3390/ijms26115348
APA StyleKindberg, K. M., Nordeng, J., Langseth, M. S., Schandiz, H., Roald, B., Solheim, S., Seljeflot, I., Stokke, M. K., & Helseth, R. (2025). IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI. International Journal of Molecular Sciences, 26(11), 5348. https://doi.org/10.3390/ijms26115348