Aims Elevated dsDNA levels in STEMI patients are associated with increased infarct size and worse clinical outcomes. However, the direct effect of dsDNA on platelet activation remains unclear. This study aims to investigate the direct influence of dsDNA on platelet activation, thrombosis, and the underlying mechanisms. Methods and Results Analysis of clinical samples revealed elevated plasma dsDNA levels in STEMI patients, which positively correlated with platelet aggregation and markers of neutrophil extracellular traps (NETs) such as MPO-DNA and CitH3. Platelet assays demonstrated the activation of the cGAS-STING pathway in platelets from STEMI patients. DsDNA directly potentiated platelet activation and thrombus formation. Mechanistic studies using G150 (cGAS inhibitor), H151 (STING inhibitor), and MCC950 (NLRP3 inhibitor), as well as cGAS-/-, STING-/- and NLRP3-/- mice showed that dsDNA activated cGAS, a previously unreported DNA sensor in platelets, and induced activation of the STING/NLRP3/caspase-1/IL-1β axis. This cascade enhanced platelet activation and thrombus formation. Platelet cGAS depletion or Palbociclib, a cGAS-STING inhibitor, approved by the FDA for advanced breast cancer, ameliorated myocardial ischemia-reperfusion injury in ApoE-/- mice fed with a high-fat diet for 12 weeks. Conclusions These results suggested that dsDNA is a novel driver of platelet activation and thrombus formation in STEMI patients. Translational Perspective ST-elevated myocardial infarction (STEMI) patients exhibit high levels of plasma double-stranded DNA (dsDNA), which directly potentiates platelet activation through the platelet cGAS/STING/NLRP3/caspase-1/IL-1β signaling pathway. STEMI patients may benefit from cGAS inhibition in the prevention of platelet hyperactivity and thrombus formation.

中文翻译：

---

双链 DNA 通过环 GMP-AMP 合酶增强血小板活化、血栓形成和心肌损伤


STEMI 患者 dsDNA 水平升高与梗塞面积增大和临床结果较差相关。然而，dsDNA 对血小板活化的直接影响仍不清楚。本研究旨在探讨双链DNA对血小板活化、血栓形成的直接影响及其潜在机制。方法和结果 临床样本分析显示 STEMI 患者血浆 dsDNA 水平升高，与血小板聚集和中性粒细胞胞外陷阱 (NET) 标记物（如 MPO-DNA 和 CitH3）呈正相关。血小板检测表明 STEMI 患者血小板中 cGAS-STING 通路被激活。双链DNA直接增强血小板活化和血栓形成。使用 G150（cGAS 抑制剂）、H151（STING 抑制剂）和 MCC950（NLRP3 抑制剂）以及 cGAS-/-、STING-/- 和 NLRP3-/- 小鼠进行的机制研究表明，dsDNA 激活了 cGAS，这是一种以前未报道的 DNA血小板中的传感器，并诱导 STING/NLRP3/caspase-1/IL-1β 轴的激活。这种级联增强了血小板活化和血栓形成。血小板 cGAS 耗竭或 Palbociclib（一种 cGAS-STING 抑制剂）经 FDA 批准用于治疗晚期乳腺癌，可改善高脂饮食喂养 12 周的 ApoE-/- 小鼠的心肌缺血再灌注损伤。结论 这些结果表明 dsDNA 是 STEMI 患者血小板活化和血栓形成的新驱动因素。 ST 抬高型心肌梗死 (STEMI) 患者血浆双链 DNA (dsDNA) 水平较高，可通过血小板 cGAS/STING/NLRP3/caspase-1/IL-1β 信号通路直接增强血小板活化。 STEMI 患者可能受益于 cGAS 抑制，以预防血小板过度活跃和血栓形成。