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

During atherosclerosis development, nicotine and its alpha 1 nicotinic acetylcholine receptors (nAChR alpha 1) 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/nAChR alpha 1-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. nAChR alpha 1 knockdown significantly decreases the nicotine-induced upregulation of p-STAT3, p-Akt and p-mTOR in vitro, while nAChR alpha 1 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 nAChR alpha 1 that modulates STAT3 nuclear translocation and its binding to the Akt promoter region upon nicotine exposure. Taken together, STAT3 and nAChR alpha 1 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.