Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.
Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.
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DOI：
10.1093/eurheartj/ehad787
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发表时间：
2023-12
影响因子：
39.3
通讯作者：
Zheng Dong;Lei Hou;Wei Luo;Li-Hong Pan;Xiao Li;Haipeng Tan;Run-Da Wu;Hao Lu;Kang Yao;Man-Di Mu;Chen-Shan Gao;Xinyu Weng;Junbo Ge
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作者：
Zheng Dong;Lei Hou;Wei Luo;Li-Hong Pan;Xiao Li;Haipeng Tan;Run-Da Wu;Hao Lu;Kang Yao;Man-Di Mu;Chen-Shan Gao;Xinyu Weng;Junbo Ge
背景和目的急性冠状动脉综合征的幸存者面临着动脉粥样硬化相关血管事件复发的高风险，尽管先进的药物治疗。根本原因尚不清楚。本研究旨在探讨心肌梗死（MI）诱导的单核细胞训练免疫是否能维持致动脉粥样硬化的特性并加速动脉粥样硬化。方法采用ApoE-/-小鼠和过继骨髓移植嵌合体小鼠，分别建立MI模型和心肌缺血再灌注模型。随后实施12周高脂饮食（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LDL（oxLDL）刺激后表现出脾酪氨酸激酶（SYK）、赖氨酸甲基转移酶5A（KMT 5A）和CCHC型锌指核酸结合蛋白（CNBP）表达升高。MI诱导的训练性免疫可通过骨髓移植传播，以加速幼稚受体的动脉粥样硬化。KMT 5A特异性地将组蛋白H4的Lys 20（H4 K20 me）的单甲基化募集到SYK的基因体，并协同反式激活SYK与CNBP。体内小干扰RNA（siRNA）抑制KMT 5A或CNBP可能减缓MI后动脉粥样硬化。6-羟基多巴胺交感神经切除减少心肌梗死后动脉粥样硬化和炎症。ST段抬高型心肌梗死（STEMI）患者的经典单核细胞与先进的冠状动脉病变表达较高的SYK和KMT 5A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子。
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.