Background and Aims Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. Methods Apolipoprotein-E deficient (ApoE−/−) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia–reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. Results In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels. Conclusions The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.

中文翻译：

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心肌梗塞驱动单核细胞的训练有素的免疫力，加速动脉粥样硬化


背景和目标 尽管采取了先进的医学治疗，急性冠脉综合征的幸存者仍面临着动脉粥样硬化相关血管事件复发的较高风险。根本原因尚不清楚。本研究旨在探讨心肌梗死 (MI) 诱导的单核细胞免疫力是否能够维持促动脉粥样硬化特征并加速动脉粥样硬化。方法 载脂蛋白 E 缺陷 (ApoE−/−) 小鼠和过继性骨髓移植嵌合小鼠接受 MI 或心肌缺血再灌注 (IR)。随后实施了为期 12 周的高脂饮食 (HFD) 方案，以阐明单核细胞训练免疫背后的机制。此外，通过流式细胞术分析了入组患者血液中的经典单核细胞。结果 在 MI 和 IR 小鼠中，血液单核细胞和骨髓来源的巨噬细胞在暴露于HFD 或氧化低密度脂蛋白 (oxLDL) 刺激。心肌梗死诱导的训练有素的免疫力可通过骨髓移植传播，以加速初始接受者的动脉粥样硬化。 KMT5A 特异性地将组蛋白 H4 (H4K20me) 的 Lys20 单甲基化招募到 SYK 的基因体上，并与 CNBP 协同反式激活 SYK。体内小干扰 RNA (siRNA) 抑制 KMT5A 或 CNBP 可能会减缓 MI 后动脉粥样硬化。 6-羟基多巴胺去交感神经可减少心肌梗死后的动脉粥样硬化和炎症。患有晚期冠状动脉病变的 ST 段抬高型心肌梗死 (STEMI) 患者的经典单核细胞表达较高的 SYK 和 KMT5A 基因水平。 结论 研究结果强调了单核细胞训练的免疫在 MI 后加速动脉粥样硬化中的关键作用，这意味着血液经典单核细胞中的 SYK 可能作为 STEMI 患者动脉粥样硬化进展的预测因素。