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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:143.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Nicotine Induces Proinflammatory Responses in Macrophages and the Aorta Leading to Acceleration of Atherosclerosis in Low-Density Lipoprotein Receptor^–/– Mice

Paul P. Lau; Lan Li; Aksam J. Merched; Alan L. Zhang; Kerry W.S. Ko; Lawrence Chan

From the Section of Diabetes, Endocrinology, and Metabolism, Departments of Medicine (P.P.L., L.C.) and Molecular and Cellular Biology (L.L., A.J.M., A.L.Z., K.W.S.K., L.C.), Baylor College of Medicine, and St. Luke’s Episcopal Hospital (L.C.), Houston, Texas.

Correspondence to Lawrence Chan, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail lchan{at}bcm.tmc.edu

Objective— We investigated the molecular mechanism of nicotine-accelerated atherosclerosis in a hyperlipidemic low-density lipoprotein receptor^–/– mouse model.

Methods and Results— Low-density lipoprotein receptor^–/– mice received time-release nicotine or placebo pellets for 90 days. Aortic lesion size was 2.5 times larger in nicotine-treated than in placebo-treated mice (P<0.001). A mild increase in lipids was seen in treated mice. We quantified 18 different serum cytokines and found a significant increase of tumor necrosis factor , interleukin 1ß, and keratinocyte-derived chemokine in nicotine-treated mice. Among 107 nuclear factor B (NF-B) target genes screened from the aorta, we found that nicotine treatment upregulated only 4 atherogenic genes including vascular adhesion molecule 1 and cyclooxygenase 2 on day 60 and platelet-derived growth factor B and platelet 12-lipoxygenase on day 90. At the cellular level, nicotine induced tumor necrosis factor and inducible nitric oxide synthase expression in RAW264.7 cells via the nicotinic acetylcholine receptors. Induction was confirmed in peritoneal macrophages isolated from nicotine-treated mice. Finally, we showed that preconditioned medium from nicotine-treated RAW264.7 cells activated NF-B in human smooth muscle cells and vascular endothelial cells as evidenced by nuclear localization and electromobility shift assay.

Conclusions— Chronic nicotine exposure augments atherosclerosis by enhancing the production of proinflammatory cytokines by macrophages, which, in turn, activate atherogenic NF-B target genes in the aortic lesions.

We investigated the molecular mechanism of nicotine-accelerated atherosclerosis in the hyperlipidemic LDLR^–/– mouse model. Our findings reveal a novel mechanism of nicotine-mediated atherogenesis. Nicotine directly activates macrophages via the nicotinic acetylcholine receptor, activating multiple downstream events, leading to NF-B–mediated inflammation in the arterial wall and accelerated atherosclerosis.

Key Words: nicotine • atherosclerosis • inflammation • macrophages • NF-kB

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