BACKGROUND:Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates the phenotypic transition of macrophages; however, the precise mechanisms governing metabolic reprogramming of cardiac reparative macrophages remain poorly understood. In this study, we investigated the role of NPM1 (nucleophosmin 1) in the metabolic and phenotypic shift of cardiac macrophages in the context of MI and explored the therapeutic effect of targeting NPM1 for ischemic tissue repair.METHODS:Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI to explore NPM1 expression and its correlation with prognostic indicators. Through RNA sequencing, metabolite profiling, histology, and phenotype analyses, we investigated the role of NPM1 in postinfarct cardiac repair using macrophage-specific NPM1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and phenotype transition of NPM1-deficient cardiac macrophages. The therapeutic efficacy of antisense oligonucleotide and inhibitor targeting NPM1 was then assessed in wild-type mice with MI.RESULTS:NPM1 expression was upregulated in the peripheral blood mononuclear cells from patients with MI that closely correlated with adverse prognostic indicators of MI. Macrophage-specific NPM1 deletion reduced infarct size, promoted angiogenesis, and suppressed tissue fibrosis, in turn improving cardiac function and protecting against adverse cardiac remodeling after MI. Furthermore, NPM1 deficiency boosted the reparative function of cardiac macrophages by shifting macrophage metabolism from the inflammatory glycolytic system to oxygen-driven mitochondrial energy production., The oligomeric NPM1 mechanistically recruited histone demethylase KDM5b to the promoter of Tsc1 (TSC complex subunit 1), the mTOR (mechanistic target of rapamycin kinase) complex inhibitor, reduced histone H3K4me3 modification, and inhibited TSC1 expression, which then facilitated mTOR-related inflammatory glycolysis and antagonized the reparative function of cardiac macrophages. The in vivo administration of antisense oligonucleotide targeting NPM1 or oligomerization inhibitor NSC348884 substantially ameliorated tissue injury and enhanced cardiac recovery in mice after MI.CONCLUSIONS:Our findings uncover the key role of epigenetic factor NPM1 in impeding postinfarction cardiac repair by remodeling metabolism pattern and impairing the reparative function of cardiac macrophages. NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for heart failure after MI.

中文翻译：

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靶向 NPM1 通过重编程修复性巨噬细胞代谢从表观遗传学角度促进梗死后心脏修复

背景：修复性巨噬细胞在心肌梗死（MI）后限制过度纤维化和促进心脏修复方面发挥着至关重要的作用，凸显了增强其修复表型对伤口愈合的重要性。代谢适应协调巨噬细胞的表型转变；然而，控制心脏修复巨噬细胞代谢重编程的精确机制仍然知之甚少。在本研究中，我们研究了 MI 背景下 NPM1（核磷蛋白 1）在心脏巨噬细胞代谢和表型转变中的作用，并探讨了靶向 NPM1 修复缺血组织的治疗效果。健康个体和 MI 患者探讨 NPM1 表达及其与预后指标的相关性。通过 RNA 测序、代谢物分析、组织学和表型分析，我们使用巨噬细胞特异性 NPM1 敲除小鼠研究了 NPM1 在梗塞后心脏修复中的作用。进行表观遗传实验来研究 NPM1 缺陷的心脏巨噬细胞代谢重编程和表型转变的机制。然后在患有 MI 的野生型小鼠中评估反义寡核苷酸和靶向 NPM1 的抑制剂的治疗效果。结果：MI 患者的外周血单核细胞中 NPM1 表达上调，与 MI 的不良预后指标密切相关。巨噬细胞特异性 NPM1 缺失可减少梗塞面积、促进血管生成并抑制组织纤维化，从而改善心脏功能并防止 MI 后发生不良心脏重塑。此外，NPM1 缺陷通过将巨噬细胞代谢从炎性糖酵解系统转移到氧驱动的线粒体能量产生，增强了心脏巨噬细胞的修复功能。寡聚 NPM1 机械地招募组蛋白去甲基酶 KDM5b 到 Tsc1（TSC 复合体亚基1 ）的启动子， mTOR（雷帕霉素激酶的机械靶标）复合物抑制剂，减少组蛋白 H3K4me3 修饰，并抑制 TSC1 表达，从而促进 mTOR 相关的炎症糖酵解并拮抗心脏巨噬细胞的修复功能。体内施用靶向 NPM1 的反义寡核苷酸或寡聚化抑制剂 NSC348884 可显着改善 MI 后小鼠的组织损伤并增强心脏恢复。结论：我们的研究结果揭示了表观遗传因子 NPM1 通过重塑代谢模式和损害心肌梗死后心脏修复的关键作用。心脏巨噬细胞的修复功能。NPM1 可能作为一种有前途的预后生物标志物和 MI 后心力衰竭的有价值的治疗靶点。