title: The activation of mTOR is required for monocyte pro-inflammatory response in patients with coronary artery disease.
abstract: 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.
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Gao
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: †Department of Cardiology, Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710004, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: ‡Department of Pharmaceutics, Tangdu Hospital, Fourth Military Medical University, Shaanxi Xi'an 710038, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Liu
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Tian
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Xi'an 710061, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
mesh_terms: D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; D010768:Phosphoserine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases