Nicotine induces proinflammatory responses in macrophages and the aorta leading to acceleration of atherosclerosis in low-density lipoprotein receptor(-/-) mice.
OBJECTIVE
We investigated the molecular mechanism of nicotine-accelerated atherosclerosis in a hyperlipidemic low-density lipoprotein receptor(-/-) mouse model.


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 alpha, interleukin 1beta, and keratinocyte-derived chemokine in nicotine-treated mice. Among 107 nuclear factor kappaB (NF-kappaB) 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 alpha 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-kappaB 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-kappaB target genes in the aortic lesions.
Lau
Paul P
PP
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Li
Lan
L
Merched
Aksam J
AJ
Zhang
Alan L
AL
Ko
Kerry W S
KW
Chan
Lawrence
L
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006937:Hypercholesterolemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000097:blood; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D018722:Nicotinic Agonists; D020574:Proto-Oncogene Proteins c-sis; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C074302:keratinocyte-derived chemokines; D009538:Nicotine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2