Kindberg Kristine Mørk, Nordeng Jostein, Langseth Miriam Sjåstad, Schandiz Hossein, Roald Borghild, Solheim Svein, Seljeflot Ingebjørg, Stokke Mathis Korseberg, Helseth Ragnhild
Oslo Center for Clinical Heart Research, Department of Cardiology Ullevaal, Oslo University Hospital, 0450 Oslo, Norway.
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, 0450 Oslo, Norway.
Int J Mol Sci. 2025 Jun 2;26(11):5348. doi: 10.3390/ijms26115348.
Inflammation contributes to myocardial injury in ST-elevation myocardial infarction (STEMI). Interleukin-6 receptor (IL-6R) inhibition has been shown to mitigate myocardial injury and reduce levels of the prothrombotic and inflammatory mediator, neutrophil extracellular traps (NETs). The enzyme peptidylarginine deiminase 4 (PAD4) is central in NET formation. We hypothesized that PAD4 links IL-6R activation and NET formation.
We conducted thrombus aspiration and peripheral blood sampling in 33 STEMI patients. In thrombi and leukocytes, we quantified the mRNA of IL-6, IL-6R, and PAD4. In peripheral blood, the protein levels of IL-6, IL-6R, PAD4, dsDNA, H3Cit, MPO-DNA, and troponin T were quantified.
In thrombi and circulating leukocytes, PAD4 mRNA was associated with IL-6R mRNA (thrombi: β = 0.34, 95% CI [0.16-0.53], = 0.001, circulating leukocytes: β = 0.92, 95% CI [0.07-1.77], = 0.036). There were no correlations between PAD4 and IL-6 in thrombi and leukocytes. The protein levels of IL-6R were associated with the NET marker H3Cit (r = 0.40, = 0.02). In thrombi, PAD4 mRNA was associated with high levels of troponin T (β = 1.15 95% CI [0.27-2.04], = 0.013).
We demonstrate an association between PAD4, IL-6R, and troponin release in STEMI patients. Our findings indicate a PAD4-mediated connection between IL-6R and NET formation and highlight PAD4 as a potential treatment target for mitigating inflammation and myocardial injury in STEMI.
炎症会导致ST段抬高型心肌梗死（STEMI）中的心肌损伤。白细胞介素-6受体（IL-6R）抑制已被证明可减轻心肌损伤，并降低促血栓形成和炎症介质中性粒细胞胞外陷阱（NETs）的水平。酶肽基精氨酸脱亚氨酶4（PAD4）在NET形成中起核心作用。我们假设PAD4连接IL-6R激活和NET形成。
我们对33例STEMI患者进行了血栓抽吸和外周血采样。在血栓和白细胞中，我们对IL-6、IL-6R和PAD4的mRNA进行了定量。在外周血中，对IL-6、IL-6R、PAD4、双链DNA、瓜氨酸化组蛋白H3（H3Cit）、髓过氧化物酶-DNA（MPO-DNA）和肌钙蛋白T的蛋白质水平进行了定量。
在血栓和循环白细胞中，PAD4 mRNA与IL-6R mRNA相关（血栓：β = 0.34，95%置信区间[0.16 - 0.53]，P = 0.001；循环白细胞：β = 0.92，95%置信区间[0.07 - 1.77]，P = 0.036）。在血栓和白细胞中，PAD4与IL-6之间无相关性。IL-6R的蛋白质水平与NET标志物H3Cit相关（r = 0.40，P = 0.02）。在血栓中，PAD4 mRNA与高水平的肌钙蛋白T相关（β = 1.15，95%置信区间[0.27 - 2.04]，P = 0.013）。
我们证明了STEMI患者中PAD4、IL-6R和肌钙蛋白释放之间的关联。我们的研究结果表明PAD4介导了IL-6R与NET形成之间的联系，并突出了PAD4作为减轻STEMI炎症和心肌损伤的潜在治疗靶点。
Zotero 插件