Nicotine Induces Proinflammatory Responses in Macrophages and the Aorta Leading to Acceleration of Atherosclerosis in Low-Density Lipoprotein Receptor-/- Mice (original) (raw)

2006, Arteriosclerosis, Thrombosis, and Vascular Biology

Objective-We investigated the molecular mechanism of nicotine-accelerated atherosclerosis in a hyperlipidemic low-density lipoprotein receptor Ϫ/Ϫ mouse model. Methods and Results-Low-density lipoprotein receptor Ϫ/Ϫ 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 (PϽ0.001). 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 1␤, 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. (Arterioscler Thromb Vasc Biol. 2006;26:143-149.)

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