Aims Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear. Methods and Results MiRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells (PBMCs) from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxLDL-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation (lL-1β, TNF-a, IL-6). Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signaling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes. Conclusion These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

中文翻译：

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miR-369-3p通过调节巨噬细胞琥珀酸-GPR91信号改善糖尿病相关动脉粥样硬化

目的 糖尿病导致巨噬细胞免疫代谢失调，加速动脉粥样硬化的进展。确定恢复代谢改变和促进炎症消退的关键因素仍然是一个未实现的目标。 MicroRNA (miR) 在巨噬细胞中协调多种信号传导事件，但其在糖尿病相关动脉粥样硬化中的治疗潜力仍不清楚。方法和结果 miRNA 分析显示，采用高脂蔗糖 (HFSC) 饮食 12 周的 Ldlr-/- 小鼠主动脉内膜病变中 miR-369-3p 表达显着降低。患有冠状动脉疾病 (CAD) 的糖尿病患者的外周血单核细胞 (PBMC) 中的 miR-369-3p 也有所减少。细胞类型表达谱显示主动脉巨噬细胞中 miR-369-3p 富集。在体外，oxLDL 治疗降低了小鼠骨髓源性巨噬细胞 (BMDM) 中 miR-369-3p 的表达。 BMDM 的代谢谱显示，miR-369-3p 过表达可阻断 oxLDL 介导的细胞代谢物琥珀酸增加，并减少线粒体呼吸 (OXPHOS) 和炎症 (IL-1β、TNF-a、IL-6)。从机制上讲，miR-369-3p 靶向琥珀酸受体 (GPR91)，并减轻 oxLDL 诱导的炎症小体信号通路激活。在 HFSC 喂养的 Ldlr-/- 小鼠中治疗性施用 miR-369-3p 模拟物可减少病变巨噬细胞中的 GPR91 表达和糖尿病加速的动脉粥样硬化，斑块大小和促炎性 Ly6Chi 单核细胞的减少表明这一点。 RNA-seq 分析显示，miR-369-3p 治疗小鼠的斑块巨噬细胞中有更多的促溶解途径，这与病变中巨噬细胞胞吞作用的增加一致。最后，GPR91 拮抗剂可减轻 oxLDL 诱导的糖尿病人类原代单核细胞炎症。结论 这些发现确立了 miR-369-3p 通过调节 GPR91 和巨噬细胞琥珀酸代谢来阻止糖尿病相关动脉粥样硬化的治疗作用。