1. Academic Validation
  2. Varenicline promotes endothelial cell migration by lowering vascular endothelial-cadherin levels via the activated α7 nicotinic acetylcholine receptor-mitogen activated protein kinase axis

Varenicline promotes endothelial cell migration by lowering vascular endothelial-cadherin levels via the activated α7 nicotinic acetylcholine receptor-mitogen activated protein kinase axis

  • Toxicology. 2017 Sep 1;390:1-9. doi: 10.1016/j.tox.2017.08.006.
Mitsuhisa Koga 1 Yuki Kanaoka 1 Keita Sugiyama 1 Kaoru Ohishi 1 Yuka Ejima 1 Mami Hisanaga 1 Yasufumi Kataoka 1 Atsushi Yamauchi 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
  • 2 Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan. Electronic address: atyama@fukuoka-u.ac.jp.
Abstract

Varenicline is a widely used and effective drug for smoking cessation. Despite its efficacy, varenicline increases the risk of Cardiovascular Disease. We previously demonstrated that varenicline aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice. However, little is known about its effects in vascular endothelial cells. Therefore, we examined whether varenicline promotes migration of human umbilical vein endothelial cells (HUVECs) using the Boyden chamber assay. Varenicline (100μM) markedly promoted migration of HUVECs and decreased expression of vascular endothelial (VE)-cadherin, an endothelial adhesion molecule. Extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) signaling were markedly activated by varenicline. Methyllycaconitine (MLA; 100nM), an α7 nicotinic acetylcholine receptor (nAChR) antagonist, but not dihydro-β-erythroidine hydrobromide (DHβE; 20μM) blocked varenicline-stimulated migration and varenicline-activated ERK, p38 and JNK signaling in HUVECs. MLA (100nM), PD98059 (an ERK inhibitor; 20μM), SB203580 (a p38 inhibitor; 20μM) and SP600125 (a JNK inhibitor; 20μM) also blocked cell migration and varenicline-induced downregulation of VE-cadherin expression in HUVECs. These findings suggest that varenicline promotes HUVEC migration by lowering VE-cadherin expression due to activated ERK/p38/JNK signaling through α7 nAChR. These processes probably contribute to varenicline-aggravated atherosclerotic plaque. Hence, an increased risk of cardiovascular events upon varenicline treatment might occur and must be considered in patients with cardiovascular diseases.

Keywords

Atherosclerosis; HUVECs; Migration; Varenicline; α7 nAChR.

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