Background. Mammalian target of rapamycin (mTOR) is crucial for endothelial function. This study is aimed at assessing whether the glucagon-like peptide-1 (GLP-1) analogue liraglutide has a protective effect on endothelial function via the mTOR signaling pathway. Methods. Human umbilical vein endothelial cells (HUVECs) were administered liraglutide (100 nM) for 0, 10, 30, 60, 720, and 1440 minutes, respectively. Then, the expression and phosphorylation levels of mTOR, mTOR-Raptor complex (mTORC1), and mTOR-Rictor complex (mTORC2) were determined by Western blot and immunoprecipitation, while mTORC1 and mTORC2 expression was blocked by siRNA-Raptor and siRNA-Rictor, respectively. Akt phosphorylation was detected by Western blot. HUVECs were then incubated with liraglutide in the absence or presence of Akt inhibitor IV. Nitric oxide (NO) release was assessed by the nitrate reductase method. Phosphorylated endothelial nitric oxide synthase (eNOS), human telomerase reverse transcriptase (hTERT), and apoptosis-related effectors were assessed for protein levels by Western blot. Telomerase activity was evaluated by ELISA. Results. Sustained mTOR phosphorylation, mTORC2 formation, and mTORC2-dependent Akt phosphorylation were induced by liraglutide. In addition, eNOS phosphorylation, NO production, nuclear hTERT accumulation, and nuclear telomerase activity were enhanced by mTORC2-mediated Akt activation. Liraglutide also showed an antiapoptotic effect by upregulating antiapoptotic proteins and downregulating proapoptotic proteins in an mTORC2-Akt activation-dependent manner. Conclusion. Liraglutide significantly improves endothelial function, at least partially via the mTORC2/Akt signaling pathway.

中文翻译：

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利拉鲁肽通过 mTOR 信号通路改善内皮功能

背景。哺乳动物雷帕霉素靶蛋白 (mTOR) 对内皮功能至关重要。本研究旨在评估胰高血糖素样肽-1 (GLP-1) 类似物利拉鲁肽是否通过 mTOR 信号通路对内皮功能具有保护作用。方法. 分别给予人脐静脉内皮细胞 (HUVEC) 0、10、30、60、720 和 1440 分钟利拉鲁肽 (100 nM)。然后，通过蛋白质印迹和免疫沉淀测定 mTOR、mTOR-Raptor 复合物 (mTORC1) 和 mTOR-Rictor 复合物 (mTORC2) 的表达和磷酸化水平，而 mTORC1 和 mTORC2 的表达被 siRNA-Raptor 和 siRNA-Rictor 阻断，分别。通过蛋白质印迹检测Akt磷酸化。然后在不存在或存在 Akt 抑制剂 IV 的情况下，将 HUVEC 与利拉鲁肽一起温育。通过硝酸还原酶法评估一氧化氮 (NO) 的释放。通过蛋白质印迹评估磷酸化内皮一氧化氮合酶 (eNOS)、人端粒酶逆转录酶 (hTERT) 和凋亡相关效应物的蛋白质水平。结果。利拉鲁肽可诱导持续的 mTOR 磷酸化、mTORC2 形成和 mTORC2 依赖性 Akt 磷酸化。此外，mTORC2 介导的 Akt 激活增强了 eNOS 磷酸化、NO 产生、核 hTERT 积累和核端粒酶活性。利拉鲁肽还通过以 mTORC2-Akt 激活依赖性方式上调抗凋亡蛋白和下调促凋亡蛋白来显示抗凋亡作用。结论。利拉鲁肽显着改善内皮功能，至少部分通过 mTORC2/Akt 信号通路。