We investigated whether extracellular vesicles (EVs) produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe^−/− mice with exosomes produced by bone marrow-derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Infusions of BMDM–HG-exo increased hematopoiesis, circulating myeloid cell numbers, and atherosclerotic lesions with an accumulation of macrophage foam and apoptotic cells. Transcriptome-wide analysis of cultured macrophages treated with BMDM–HG-exo or plasma EVs isolated from subjects with type II diabetes revealed a reduced inflammatory state and increased metabolic activity. Furthermore, BMDM–HG-exo induced cell proliferation and reprogrammed energy metabolism by increasing glycolytic activity. Lastly, profiling microRNA in BMDM–HG-exo and plasma EVs from diabetic subjects with advanced atherosclerosis converged on miR-486-5p as commonly enriched and recognized in dysregulated hematopoiesis and Abca1 control. Together, our findings show that EVs serve to communicate detrimental properties of hyperglycemia to accelerate atherosclerosis in diabetes.

我们研究了在高血糖条件下产生的细胞外囊泡 （EVs） 是否可以传递信号以驱动动脉粥样硬化。我们通过用暴露于高葡萄糖 （BMDM-HG-exo） 或对照的骨髓来源的巨噬细胞 （BMDM） 产生的外泌体治疗 Apoe^-/-小鼠来做到这一点。输注 BMDM-HG-exo 增加了造血功能、循环髓系细胞数量和动脉粥样硬化病变，并伴有巨噬细胞泡沫和凋亡细胞的积累。对用 BMDM-HG-exo 或从 II 型糖尿病受试者中分离的血浆 EV 处理的培养巨噬细胞的转录组范围分析显示炎症状态降低和代谢活性增加。此外，BMDM-HG-exo 通过增加糖酵解活性诱导细胞增殖和重编程能量代谢。最后，分析来自晚期动脉粥样硬化糖尿病患者的 BMDM-HG-exo 和血浆 EVs 中的 microRNA，收敛于 miR-486-5p，通常在失调的造血和 Abca1 对照中富集和识别。总之，我们的研究结果表明，EV 有助于传达高血糖的有害特性，以加速糖尿病的动脉粥样硬化。