From the Center for Excellence in Vascular Biology (R.K., S.K., R.T., D.C.R., D.B.-G., L.S.A.P., G.K.S., P.L., M.A., K.C., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Center for Interdisciplinary Cardiovascular Sciences (H.H., M.C.B., S.A.S., M.A., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Arterioscler Thromb Vasc Biol. 2020 Aug;40(8):1838-1853. doi: 10.1161/ATVBAHA.118.314087. Epub 2020 May 28.
OBJECTIVE: Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood. Our goal was to identify that increased S100A9 promotes the release of calcification-prone extracellular vesicles from human macrophages in diabetes mellitus. Approach and Results: Human primary macrophages exposed to high glucose (25 mmol/L) increased S100A9 secretion and the expression of receptor for advanced glycation end products (RAGE) protein. Recombinant S100A9 induced the expression of proinflammatory and osteogenic factors, as well as the number of extracellular vesicles with high calcific potential (alkaline phosphatase activity, <0.001) in macrophages. Treatment with a RAGE antagonist or silencing with S100A9 siRNA in macrophages abolished these responses, suggesting that stimulation of the S100A9-RAGE axis by hyperglycemia favors a procalcific environment. We further showed that an imbalance between Nrf-2 (nuclear factor 2 erythroid related factor 2) and NF-κB (nuclear factor-κB) pathways contributes to macrophage activation and promotes a procalcific environment. In addition, streptozotocin-induced diabetic ApoeS100a9 mice and mice treated with S100a9 siRNA encapsulated in macrophage-targeted lipid nanoparticles showed decreased inflammation and microcalcification in atherosclerotic plaques, as gauged by molecular imaging and comprehensive histological analysis. In human carotid plaques, comparative proteomics in patients with diabetes mellitus and histological analysis showed that the S100A9-RAGE axis associates with osteogenic activity and the formation of microcalcification. CONCLUSIONS: Under hyperglycemic conditions, macrophages release calcific extracellular vesicles through mechanisms involving the S100A9-RAGE axis, thus contributing to the formation of microcalcification within atherosclerotic plaques.
目的：血管钙化是心血管疾病的一个危险因素，并在糖尿病中加速发展。先前的工作已经确定了易钙化的细胞外囊泡在促进血管钙化方面的作用。然而，糖尿病引发心血管事件的机制仍不完全清楚。我们的目标是确定在糖尿病中，S100A9 的增加促进了人巨噬细胞中易钙化的细胞外囊泡的释放。
方法和结果：暴露于高葡萄糖（25mmol/L）的人原代巨噬细胞增加了 S100A9 的分泌和晚期糖基化终产物受体（RAGE）蛋白的表达。重组 S100A9 诱导了前炎症和成骨因子的表达，以及具有高钙化潜力的细胞外囊泡的数量（碱性磷酸酶活性，<0.001）在巨噬细胞中增加。用 RAGE 拮抗剂处理或用 S100A9 siRNA 沉默巨噬细胞中的 S100A9 可消除这些反应，表明高血糖刺激 S100A9-RAGE 轴有利于形成促钙化环境。我们进一步表明，Nrf-2（核因子 2 红细胞相关因子 2）和 NF-κB（核因子-κB）通路之间的失衡导致巨噬细胞激活，并促进了促钙化环境的形成。此外，链脲佐菌素诱导的糖尿病 ApoeS100a9 小鼠和用包裹在巨噬细胞靶向脂质纳米颗粒中的 S100a9 siRNA 治疗的小鼠，通过分子成像和综合组织学分析显示，动脉粥样硬化斑块中的炎症和微钙化减少。在人类颈动脉斑块中，糖尿病患者的比较蛋白质组学和组织学分析表明，S100A9-RAGE 轴与成骨活性和微钙化的形成有关。
结论：在高血糖条件下，巨噬细胞通过涉及 S100A9-RAGE 轴的机制释放易钙化的细胞外囊泡，从而有助于在动脉粥样硬化斑块内形成微钙化。
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