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.
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Authors | Shanshan Gao, Weimin Liu, Xiaozhen Zhuo, Lijun Wang, Gang Wang, Tao Sun, Zhao Zhao, Junhui Liu, Yuling Tian, Juan Zhou, Zuyi Yuan, Yue Wu |
Journal | Clinical science (London, England : 1979)
(Clin Sci (Lond))
Vol. 128
Issue 8
Pg. 517-26
(Apr 2015)
ISSN: 1470-8736 [Electronic] England |
PMID | 25428582
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Inflammation Mediators
- Lipoproteins, LDL
- NF-kappa B
- oxidized low density lipoprotein
- Phosphoserine
- MTOR protein, human
- TOR Serine-Threonine Kinases
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Topics |
- Coronary Artery Disease
(blood, drug therapy, enzymology, pathology)
- Enzyme Activation
(drug effects)
- Female
- Gene Knockdown Techniques
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
(pharmacology, therapeutic use)
- Inflammation
(metabolism, pathology)
- Inflammation Mediators
(metabolism)
- Lipoproteins, LDL
(metabolism)
- Male
- Middle Aged
- Monocytes
(enzymology, pathology)
- NF-kappa B
(metabolism)
- Phosphorylation
(drug effects)
- Phosphoserine
(metabolism)
- Protein Binding
(drug effects)
- Signal Transduction
(drug effects)
- TOR Serine-Threonine Kinases
(metabolism)
- Time Factors
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