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

• Published in: Toxicology (Amsterdam) Vol. 380; pp. 62 - 71
• Main Authors: Kanaoka, Yuki, Koga, Mitsuhisa, Sugiyama, Keita, Ohishi, Kaoru, Kataoka, Yasufumi, Yamauchi, Atsushi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-04-2017
• Subjects: Atherosclerosis; Emergency; oxLDL uptake; Scavenger receptor; Varenicline; α7 nAChR; ABC; scavenger receptor; MLA; high-density lipoprotein; oxLDL uptake; cluster of differentiation 36; LOX-1; varenicline; HDL; NF-κB; dihydro-β-erythroidine hydrobromide; nAChR; oxLDL; CD36; scavenger receptor class A; extracellular signal-regulated kinase 1/2; nicotinic acetylcholine receptor; atherosclerosis; α 7 nAChR; nuclear factor-kappa B; lectin-like oxidized LDL receptor-1; methyllycaconitine; ERK1/2; SR-A; adenosine triphosphate-binding cassette transporters; DHβE; oxidized low-density lipoprotein; Scavenger receptor; Varenicline; α7 nAChR; Atherosclerosis
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2017.02.006

Abstract 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 (1–10 μM) 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 (10 μM) 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, methyllycacinitine (50 nM), but not by an α4β2 nAChR antagonist, dihydro-β-erythroidine hydrobromide (1 μM). These data suggest that varenicline promotes oxLDL uptake by upregulating of 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).