Department of Cardiac Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Department of Ultrasound, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Mol Med Rep. 2020 Dec;22(6):5293-5303. doi: 10.3892/mmr.2020.11595. Epub 2020 Oct 14.
S100 calcium binding protein A8 (S100A8) and A9 (S100A9) belong to the S100 family of calcium‑binding proteins and have important roles in inflammation. They increase endothelial cell proliferation, thereby affecting inflammation, angiogenesis and tumorigenesis. However, the mechanism of action of S100A8/9 in endothelial cells needs further study. Therefore, the present study sought to investigate the effects of S100A8/9 on the proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) and their mechanism of action. The viability of HUVECs was determined through a Cell Counting Kit‑8 assay. The effect of S100A8/9 on the proliferation of HUVECs was detected by flow cytometry. Migration was evaluated by a Transwell migration assay. Apoptosis was evaluated by Annexin V‑FITC and PI staining via flow cytometry. Western blot analysis and reverse transcription‑quantitative polymerase chain reaction assays were performed to evaluate the activation of the phosphatidylinositol 3‑phosphate kinase (PI3K)/Akt/mTOR pathway and mTOR complex 2 (mTORC2). We previously confirmed that S100A8/9 were consistently overexpressed at 1 and 7 days post‑surgery in a rabbit vein graft model, which is the period when apoptosis changes to proliferation in neointimal hyperplasia. In the present study, proliferation, viability and migration were increased after treating HUVECs with S100A8/9. S100A8/9 stimulated the PI3K/Akt/mTOR pathway and mTORC2, which was significantly suppressed by a receptor for advanced glycation end products (RAGE)‑blocking antibody. Furthermore, depleting expression of RAGE or mTORC2 protein components (rapamycin‑insensitive companion of mTOR) by small interfering RNA was found to reduce the cell viability, migration and angiogenesis of S100A8/9‑treated HUVECs. The development of neointimal hyperplasia is a complex process initiated by damage to endothelial cells. In conclusion, S100A8/9 has an important role in intimal hyperplasia by promoting cell growth and angiogenesis via RAGE signaling and activation of mTORC2.
S100 钙结合蛋白 A8（S100A8）和 A9（S100A9）属于 S100 钙结合蛋白家族，在炎症中具有重要作用。它们促进内皮细胞增殖，从而影响炎症、血管生成和肿瘤发生。然而，S100A8/9 在内皮细胞中的作用机制仍需进一步研究。因此，本研究旨在探讨 S100A8/9 对人脐静脉内皮细胞（HUVEC）增殖和血管生成的影响及其作用机制。通过细胞计数试剂盒-8 检测 HUVEC 的活力。通过流式细胞术检测 S100A8/9 对 HUVEC 增殖的影响。通过 Transwell 迁移实验评估迁移。通过 Annexin V-FITC 和 PI 染色通过流式细胞术评估细胞凋亡。通过 Western blot 分析和逆转录-定量聚合酶链反应检测磷酸肌醇 3-激酶（PI3K）/Akt/mTOR 途径和 mTOR 复合物 2（mTORC2）的激活。我们之前在兔静脉移植物模型中证实，S100A8/9 在术后 1 天和 7 天持续高表达，这是在内皮细胞凋亡向新生内膜增生中增殖改变的时期。在本研究中，用 S100A8/9 处理 HUVEC 后，细胞增殖、活力和迁移增加。S100A8/9 刺激 PI3K/Akt/mTOR 途径和 mTORC2，而 RAGE 阻断抗体显著抑制 mTORC2。此外，通过小干扰 RNA 耗尽 RAGE 或 mTORC2 蛋白成分（rapamycin-insensitive companion of mTOR）的表达，发现减少 S100A8/9 处理的 HUVEC 的细胞活力、迁移和血管生成。新生内膜增生的发展是内皮细胞损伤引发的复杂过程。综上所述，S100A8/9 通过 RAGE 信号转导和 mTORC2 的激活促进细胞生长和血管生成，在血管内膜增生中起重要作用。
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