Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA.
Cardiovasc Res. 2024 Nov 25;120(14):1693-1712. doi: 10.1093/cvr/cvae102.
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 orchestrate multiple signalling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear.
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 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 oxidized low density lipoprotein (oxLDL)-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation [Interleukin (lL)-1β, TNF-α, and IL-6]. Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signalling 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.
These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.
糖尿病导致巨噬细胞免疫代谢失调，加速动脉粥样硬化进展。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满足的目标。microRNAs 协调巨噬细胞中的多种信号事件，但它们在糖尿病相关动脉粥样硬化中的治疗潜力尚不清楚。
miRNA 谱分析显示，在高脂肪蔗糖饮食喂养 12 周的 Ldlr-/-小鼠主动脉内膜病变中，miR-369-3p 的表达显著降低。患有冠心病的糖尿病患者的外周血单核细胞中也降低了 miR-369-3p 的表达。细胞类型表达谱显示 miR-369-3p 在主动脉巨噬细胞中富集。在体外，oxLDL 处理降低了小鼠骨髓来源巨噬细胞（BMDM）中 miR-369-3p 的表达。BMDM 中的代谢谱分析显示，miR-369-3p 的过表达阻断了氧化低密度脂蛋白（oxLDL）介导的细胞代谢物琥珀酸的增加，并降低了线粒体呼吸（OXPHOS）和炎症[白细胞介素（IL）-1β、TNF-α 和 IL-6]。在机制上，miR-369-3p 靶向琥珀酸受体（GPR91），减轻 oxLDL 诱导的炎症小体信号通路的激活。在 HFSC 喂养的 Ldlr-/-小鼠中，给予 miR-369-3p 模拟物治疗，可降低病变巨噬细胞中的 GPR91 表达和糖尿病加速的动脉粥样硬化，表现为斑块大小和促炎 Ly6Chi 单核细胞减少。RNA-Seq 分析显示，miR-369-3p 处理的斑块巨噬细胞中具有更多的促解决途径，与病变中巨噬细胞吞噬作用的增加一致。最后，GPR91 拮抗剂减弱了糖尿病患者原代单核细胞中 oxLDL 诱导的炎症。
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。
