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Toxicology. 2017 Apr 1;380:62-71. doi: 10.1016/j.tox.2017.02.006. Epub 2017 Feb 12.

Varenicline enhances oxidized LDL uptake by increasing expression of LOX-1 and CD36 scavenger receptors through α7 nAChR in macrophages.

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Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan. Electronic address:


Varenicline is a widely used and effective drug for smoking cessation. It is a partial agonist of the α4β2 nicotinic acetylcholine receptor (nAChR) and full agonist of α7 nAChR. We have reported that varenicline aggravates formation of atherosclerotic plaques through α7 nAChR in apolipoprotein E knockout mice. However, little is known about its effects on macrophages in atherosclerotic plaques. Here, we ascertained whether varenicline promotes oxidized low-density lipoprotein (oxLDL) uptake in mouse peritoneal macrophages in vitro and clarified its mechanism. We investigated the effects of varenicline (1-10μM) on expression of scavenger receptors (lectin-like oxidized LDL receptor-1 (LOX-1), cluster of differentiation (CD) 36 and scavenger receptor class A (SR-A)) in RAW264.7 cells. Expression of protein and mRNA was determined by western blotting and real-time quantitative reverse transcription-polymerase chain reaction, respectively. Effects of varenicline (10μM) on oxLDL uptake were examined by counting the number of macrophages stained with oil red O and hematoxylin. Varenicline significantly increased expression of the protein and mRNA of LOX-1 and CD36, but not SR-A, in RAW264.7 cells, and increased oxLDL uptake in macrophages. These effects of varenicline were blocked significantly by an α7 nAChR antagonist, methyllycaconitine (MLA) (50nM), but not by an α4β2 nAChR antagonist, dihydro-β-erythroidine hydrobromide (DHβE) (1μM). These data suggest that varenicline promotes oxLDL uptake by upregulating expression of LOX-1 and CD36 through α7 nAChR in macrophages. We found that varenicline significantly activated extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-kappa B (NF-κB) signaling pathways in RAW264.7 cells. This activation was blocked by MLA but not DHβE. Therefore, ERK1/2-NF-κB signaling pathway is highly likely to be responsible for varenicline-induced upregulation of LOX-1 and CD36 expression through α7 nAChR in macrophages. These processes probably contribute to varenicline-aggravated atherosclerotic plaque formation. Hence, an increased risk of cardiovascular events upon varenicline treatment could occur, and must be considered in patients (especially those suffering from cardiovascular diseases).


Atherosclerosis; Scavenger receptor; Varenicline; oxLDL uptake; α(7) nAChR

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