Research Paper Volume 11, Issue 19 pp 8120—8138

The interaction between STAT3 and nAChRα1 interferes with nicotine-induced atherosclerosis via Akt/mTOR signaling cascade

Shuang Xu 1, *, , Huaner Ni 1, *, , Hangwei Chen 1, , Qiuyan Dai 1, ,

  • 1 Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
* Equal contribution

received: August 14, 2019 ; accepted: September 14, 2019 ; published: October 14, 2019 ;
How to Cite

Copyright © 2019 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


During atherosclerosis development, nicotine and its α1 nicotinic acetylcholine receptors (nAChRα1) activate atherogenic inflammation. However, the effect of signal transducer and activator of transcription 3 (STAT3)-related inflammatory pathways in nicotine-induced atherosclerosis has been poorly studied. This study investigated the transcriptional mechanism of STAT3 in nicotine/nAChRα1-induced atherosclerosis. In vivo, ApoE-/- mice were used to establish an atherosclerotic model. Plaque area and composition were assessed by oil red O staining and immunohistochemistry. In vitro, vascular smooth muscle cells and macrophages were used to investigate cell migration, proliferation, inflammation and related signaling pathways by Transwell migration assay, EdU assay, immunofluorescence, western blotting, coimmunoprecipitation and chromatin immunoprecipitation. nAChRα1 knockdown significantly decreases the nicotine-induced upregulation of p-STAT3, p-Akt and p-mTOR in vitro, while nAChRα1 overexpression has the opposite effects. The inhibition of STAT3 attenuated nicotine-induced atherosclerosis, by reducing the proliferation and migration of vascular smooth muscle cells and inflammation in macrophages. Moreover, there is a direct interaction between STAT3 and nAChRα1 that modulates STAT3 nuclear translocation and its binding to the Akt promoter region upon nicotine exposure. Taken together, STAT3 and nAChRα1 blockade attenuates nicotine-induced atherosclerosis by reducing the migration and proliferation of vascular smooth muscle cells and inflammation in macrophages via the Akt/mTOR pathway.


CVD: cardiovascular disease; nAChRs: nicotinic acetylcholine receptors; nAChRα1: α1 nicotinic acetylcholine receptors; CoIP: coimmunoprecipitation; ChIP: chromatin immunoprecipitation; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; STAT3: signal transducer and activator of transcription; ERK1/2: extracellular signal-regulated kinase1/2; Akt: protein kinase B; mTOR: mechanistic target of rapamycin kinase; MMP2: matrix metallopeptidase 2; α-SMA: α-smooth muscle actin; MCP-1: monocyte chemotactic protein 1; IL-10: interleukin-10; IFN-γ: interferon-γ; MAPK: mammalian mitogen-activated protein kinase; ELISA: enzyme-linked immunosorbent assay; PCR: polymerase chain reaction; FBS: fetal bovine serum; PBS: phosphate buffered saline; VSMCs: vascular smooth muscle cells; HFD: high fat diet; NCD: normal chow diet; SBP: systolic blood pressure; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; ApoE: apolipoprotein E; AAV: adeno-associated virus.