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



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-/-KitW-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-/-KitW-sh/W-shmice reconstituted with MCs from Apoe-/-α7nAChR-/-animals.



Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis.
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.).
Chen
C
Wang
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.).
Han
H
Chen
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.).
Wei
W
Zhu
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.).
Yinchuan
Y
Xu
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.).
Mingfei
M
Liu
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.).
Lianlian
L
Zhu
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.).
Fan
F
Yang
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.).
Ling
L
Zhang
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.).
Xianbao
X
Liu
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.).
Zhiwei
Z
Zhong
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.).
Jing
J
Zhao
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.).
Jun
J
Jiang
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.).
Meixiang
M
Xiang
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.).
Hong
H
Yu
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.).
Xinyang
X
Hu
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.).
Hong
H
Lu
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.
Jian'an
J
Wang
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000172:deficiency / Q000235:genetics
D001057:Apolipoproteins E; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D003094:Collagen; D002784:Cholesterol; D019009:Proto-Oncogene Proteins c-kit
apolipoprotein E; atherosclerosis; hypercholesterolemia; mast cell; nicotine