The activation of mTOR is required for monocyte pro-inflammatory response in patients with coronary artery disease
The activation of mTOR is required for monocyte pro-inflammatory response in patients with coronary artery disease
复制标题
冠状动脉疾病患者的单核细胞促炎症反应需要 mTOR 的激活。
DOI：
10.1042/cs20140427
复制
发表时间：
2015-04-01
期刊：
影响因子：
6
通讯作者：
Wu, Yue
中科院分区：
文献类型：
--
作者：
Gao, Shanshan;Liu, Weimin;Wu, Yue
核因子-κ B（NF-κ B）是动脉粥样硬化（AS）系统性炎症的关键调节因子。哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸/苏氨酸蛋白激酶，已成为慢性炎症的重要调节因子。然而，mTOR和NF-κ B之间的关系仍然不明确。本研究的目的是研究mTOR在冠状动脉疾病（CAD）患者的人单核细胞（HMCs）的促炎通路中的作用，并确定mTOR和NF-κ B信号传导在炎症状态中的相互作用。从68例CAD患者和59例非CAD患者的空腹血液样本中分离HMCs，检测NF-κ B活性、p65核转位和mTOR磷酸化，CAD组与非CAD组相比均显著升高。冠心病组血清白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α水平高于非冠心病组。在体外实验中，将从非CAD受试者分离的HMC用作培养模型，并用从CAD患者（CAD血清）或非CAD受试者（con血清）提取的血清处理。CAD血清诱导mTOR的时间依赖性磷酸化、异常NF-κ B活化以及炎症因子的上调。此外，通过药理学或遗传学手段抑制mTOR消除了CAD血清触发的NF-κ B活化和促炎反应。此外，降脂药物他汀类药物部分阻断了CAD血清激活的mTOR和促炎反应。我们的研究结果表明，CAD患者处于促炎状态，NF-κ B结合活性增加，mTOR磷酸化增强。我们还发现mTOR的激活是HMCs通过NF-κ B依赖性通路进行促炎反应所必需的，这揭示了AS的潜在机制和临床实践中减轻AS的潜在策略。
Nuclear factor-kappa B (NF-kappa B) is a key regulator of systematic inflammation in atherosclerosis (AS). The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, has emerged as an important regulator of chronic inflammation. However, the relationship between mTOR and NF-kappa B remains poorly defined. The aim of the present study was to investigate the role of mTOR in the pro-inflammatory pathway of human monocytes (HMCs) in patients with coronary artery disease (CAD) and to determine the interaction between mTOR and NF-kappa B signalling in the inflammatory state. HMCs were isolated from fasting blood samples of 68 patients with CAD and 59 subjects without CAD (non-CAD) to test the activity of NF-kappa B, p65 nuclear translocation and mTOR phosphorylation, which were all significantly elevated in the CAD group compared with those in the non-CAD group. The concentrations of serum interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were higher in the CAD group than in the non-CAD group. In an in vitro experiment, HMCs isolated from non-CAD subjects were used as culture model and were treated with sera extracted from CAD patients (CAD sera) or non-CAD subjects (con sera). CAD sera induced time-dependent phosphorylation of mTOR, aberrant NF-kappa B activation, as well as up-regulation of inflammatory factors. Moreover, inhibition of mTOR by pharmacological or genetic means abolished the CAD sera-triggered NF-kappa B activation and pro-inflammatory response. Furthermore, lipid-lowering drug statins partly blocked the CAD sera-activated mTOR and pro-inflammatory response. Our results show that CAD patients are in the pro-inflammatory state with increased NF-kappa B binding activity and enhanced mTOR phosphorylation. We also found that the activation of mTOR is required for the pro-inflammatory response via NF-kappa B-dependent pathway in HMCs, which unveils the underlying mechanism of AS and potential strategies to attenuate AS in clinical practice.