Department of Internal Medicine, Hebei Medical University, Shijiazhuang, P.R. China.; Department of Cardiology, Hebei General Hospital, Shijiazhuang, P.R. China.
Department of Internal Medicine, Hebei Medical University, Shijiazhuang, P.R. China.; Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, P.R. China.
Tissue Cell. 2023 Jun;82:102084. doi: 10.1016/j.tice.2023.102084. Epub 2023 Apr 3.
This study aimed to investigate role of erythropoietin in atherosclerosis and explore whether underlying mechanism is associated with PI3K/AKT/mTOR pathway.
High-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice (C57BL/6 genetic background). Mice were randomly divided into the control group and the EPO group. Hematoxylin-eosin was performed for the determination of atherosclerotic lesions. The expression levels of related proteins were detected by western blot analysis.
Erythropoietin significantly enhanced the incidence of hemorrhage in atherosclerotic plaques compared with the control group. The proteins' expression signaling pathways (including PI3K, AKT, and mTOR) and angiogenesis-related proteins (VEGF, COX-2, and HIF-1α) were proved to be up-regulated by erythropoietin. Additionally, erythropoietin significantly enhanced the incidence of hemorrhage in the atherosclerotic plaques compared with the control group. The vitro experiments were conducted in macrophages at 21% O or 1% O. The data showed that expression of p-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1α related proteins increased in 1% O group than 21% O group. Moreover, compared with control group, protein expression including p-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1α was markedly increased in EPO group, decreased in inhibitors group, and similar results were observed in EPO+ inhibitors group.
The present study demonstrated that erythropoietin might promote angiogenesis in atherosclerotic vulnerable by activating PI3K/AKT/mTOR signaling pathway in atherosclerotic, providing a novel therapeutic target for atherosclerotic targeted therapy.
本研究旨在探讨促红细胞生成素在动脉粥样硬化中的作用，并探讨其潜在机制是否与 PI3K/AKT/mTOR 通路有关。
采用载脂蛋白 E 基因敲除小鼠（C57BL/6 遗传背景）建立高脂饮食诱导的动脉粥样硬化模型。将小鼠随机分为对照组和 EPO 组。采用苏木精-伊红染色法测定动脉粥样硬化病变。采用 Western blot 分析检测相关蛋白的表达水平。
与对照组相比，促红细胞生成素显著增加了动脉粥样硬化斑块中的出血发生率。促红细胞生成素还上调了 PI3K、AKT 和 mTOR 等信号通路蛋白及血管生成相关蛋白（VEGF、COX-2 和 HIF-1α）的表达。此外，与对照组相比，促红细胞生成素组的动脉粥样硬化斑块中的出血发生率显著增加。在 21% O 或 1% O 条件下进行的巨噬细胞体外实验显示，1% O 组 p-PI3K、p-AKT、p-mTOR、VEGF、COX-2 和 HIF-1α 相关蛋白的表达均高于 21% O 组。与对照组相比，EPO 组的 p-PI3K、p-AKT、p-mTOR、VEGF、COX-2 和 HIF-1α 等蛋白表达明显增加，抑制剂组的表达降低，EPO+抑制剂组的表达与抑制剂组相似。
本研究表明，促红细胞生成素可能通过激活动脉粥样硬化中的 PI3K/AKT/mTOR 信号通路促进易损斑块中的血管生成，为动脉粥样硬化的靶向治疗提供了新的治疗靶点。
