Varenicline is a widely used and effective drug for smoking cessation. It is a partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor (nAChR) and full agonist of alpha(7) nAChR. We have reported that varenicline aggravates formation of atherosclerotic plaques through alpha(7) 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 (1-10,mu M) 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 transcriptionpolymerase chain reaction, respectively. Effects of varenicline (10 mu M) on oxLDL uptake were examined by counting the number of macrophages stained with oil red 0 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 alpha 7 nAChR antagonist, methyllycaconitine (MLA) (50 nM), but not by an alpha(4)beta(2) nAChR antagonist, dihydro-beta-erythroidine hydrobromide (DH beta E) (1 AA). These data suggest that varenicline promotes oxLDL uptake by upregulating expression of LOX -1 and CD36 through alpha(7) nAChR in macrophages. We found that varenicline significantly activated extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa B (NF-kappa B) signaling pathways in RAW264.7 cells. This activation was blocked by MLA but not DH beta E. Therefore, ERK1/2-NF-kappa B signaling pathway is highly likely to be responsible for varenicline-induced upregulation of LOX-1 and CD36 expression through a(7) 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). (C) 2017 Elsevier B.V. All rights reserved.