Nuclear factor-κB (NF-κB) 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-κB 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-κB 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-κB, 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)-α 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-κB activation, as well as up-regulation of inflammatory factors. Moreover, inhibition of mTOR by pharmacological or genetic means abolished the CAD sera-triggered NF-κB 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-κB binding activity and enhanced mTOR phosphorylation. We also found that the activation of mTOR is required for the pro-inflammatory response via NF-κB-dependent pathway in HMCs, which unveils the underlying mechanism of AS and potential strategies to attenuate AS in clinical practice.
- atherosclerosis (AS)
- mammalian target of rapamycin (mTOR)
- nuclear factor-κB (NF-κB)
Abbreviations: AS, atherosclerosis; BMI, body mass index; CAD, coronary artery disease; EC, endothelial cell; HMC, human monocyte; HRP, horseradish peroxidase; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; LDL, low-density lipoprotein; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; Ox-LDL, oxidized LDL; PDTC, pyrrolidine dithiocarbamate; p-mTOR, phosphorylated mTOR; SN-50, p50 nuclear transport blocker; TLR, toll-like receptor; TNF, tumour necrosis factor
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