Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells

Chen Wang; Han Chen; Wei Zhu; Yinchuan Xu; Mingfei Liu; Lianlian Zhu; Fan Yang; Ling Zhang; Xianbao Liu; Zhiwei Zhong; Jing Zhao; Jun Jiang; Meixiang Xiang; Hong Yu; Xinyang Hu; Hong Lu; Jian'an Wang

doi:10.1161/ATVBAHA.116.307264

Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells

Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):53-65. doi: 10.1161/ATVBAHA.116.307264. Epub 2016 Nov 10.

Authors

Chen Wang¹, Han Chen¹, Wei Zhu¹, Yinchuan Xu¹, Mingfei Liu¹, Lianlian Zhu¹, Fan Yang¹, Ling Zhang¹, Xianbao Liu¹, Zhiwei Zhong¹, Jing Zhao¹, Jun Jiang¹, Meixiang Xiang¹, Hong Yu¹, Xinyang Hu¹, Hong Lu¹, Jian'an Wang²

Affiliations

¹ From the Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China (C.W., H.C., W.Z., Y.X., L. Zhu, L. Zhang, X.L., Z.Z., J.Z., J.J., M.X., H.Y., X.H., J.W.); Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China (C.W., H.C., W.Z., Y.X., M.L., L. Zhu, F.Y., L. Zhang, X.L., Z.Z., J.Z., J.J., M.X., H.Y., X.H., J.W.); and Saha Cardiovascular Research Center, Departments of Physiology, University of Kentucky, Lexington (H.L.).
² From the Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China (C.W., H.C., W.Z., Y.X., L. Zhu, L. Zhang, X.L., Z.Z., J.Z., J.J., M.X., H.Y., X.H., J.W.); Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China (C.W., H.C., W.Z., Y.X., M.L., L. Zhu, F.Y., L. Zhang, X.L., Z.Z., J.Z., J.J., M.X., H.Y., X.H., J.W.); and Saha Cardiovascular Research Center, Departments of Physiology, University of Kentucky, Lexington (H.L.). wja@zju.edu.cn.

PMID: 27834689
DOI: 10.1161/ATVBAHA.116.307264

Abstract

Objective: Cigarette smoking is an independent risk factor for atherosclerosis. Nicotine, the addictive component of cigarettes, induces mast cell (MC) release and contributes to atherogenesis. The purpose of this study was to determine whether nicotine accelerates atherosclerosis through MC-mediated mechanisms and whether MC stabilizer prevents this pathological process.

Approach and results: Nicotine administration increased the size of atherosclerotic lesions in apolipoprotein E-deficient (Apoe^-/-) mice fed a fat-enriched diet. This was accompanied by enhanced intraplaque macrophage content and lipid deposition but reduced collagen and smooth muscle cell contents. MC deficiency in Apoe^-/- mice (Apoe^-/-Kit^W-sh/W-sh) diminished nicotine-induced atherosclerosis. Nicotine activated bone marrow-derived MCs in vitro, which was inhibited by a MC stabilizer disodium cromoglycate or a nonselective nicotinic acetylcholine receptor blocker mecamylamine. Further investigation revealed that α7 nicotinic acetylcholine receptor was a target for nicotine activation in MCs. Nicotine did not change atherosclerotic lesion size of Apoe^-/-Kit^W-sh/W-sh mice reconstituted with MCs from Apoe^-/-α7nAChR^-/- animals.

Conclusions: Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis.

Keywords: apolipoprotein E; atherosclerosis; hypercholesterolemia; mast cell; nicotine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta, Thoracic / drug effects*
Aorta, Thoracic / metabolism
Aorta, Thoracic / pathology
Aortic Diseases / chemically induced*
Aortic Diseases / genetics
Aortic Diseases / metabolism
Aortic Diseases / prevention & control
Apolipoproteins E / deficiency*
Apolipoproteins E / genetics
Atherosclerosis / chemically induced*
Atherosclerosis / genetics
Atherosclerosis / metabolism
Atherosclerosis / prevention & control
Bone Marrow Transplantation
Cell Degranulation / drug effects
Cells, Cultured
Cholesterol / metabolism
Collagen / metabolism
Diet, High-Fat
Disease Models, Animal
Disease Progression
Foam Cells / drug effects
Foam Cells / metabolism
Genetic Predisposition to Disease
Macrophages, Peritoneal / drug effects
Macrophages, Peritoneal / metabolism
Male
Mast Cells / drug effects*
Mast Cells / metabolism
Mast Cells / pathology
Mice, Knockout
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Nicotine / toxicity*
Nicotinic Agonists / toxicity*
Nicotinic Antagonists / pharmacology
Phenotype
Plaque, Atherosclerotic
Proto-Oncogene Proteins c-kit / genetics
Signal Transduction / drug effects
Time Factors
alpha7 Nicotinic Acetylcholine Receptor / agonists*
alpha7 Nicotinic Acetylcholine Receptor / deficiency
alpha7 Nicotinic Acetylcholine Receptor / genetics

Substances

Apolipoproteins E
Chrna7 protein, mouse
Nicotinic Agonists
Nicotinic Antagonists
alpha7 Nicotinic Acetylcholine Receptor
Nicotine
Collagen
Cholesterol
Proto-Oncogene Proteins c-kit