Abstract
Aims:
The aim of this study was to investigate the mechanisms by which nicotine increases vascular smooth muscle cell (VSMC) proliferation and post-injury neointimal formation.
Methods and results:
Vascular injury was inflicted in the right iliac artery of nicotine-treated and control rats. Nicotine increased post-injury VSMC proliferation (Ki67(+) cells) and neointimal formation (neointima/media ratio, 0.42 ± 0.23 vs. 0.14 ± 0.07, P= 0.02). To determine the mechanisms by which nicotine exacerbates VSMC proliferation, cultured cells were exposed to nicotine, and signalling pathways leading to cell proliferation were studied. Nicotine activated extracellular signal-regulated kinase (ERK) 1/2 in a dose- and time-dependent manner. The blockade of this signalling axis abolished nicotine-mediated proliferation. Functional nicotinic acetylcholine receptors and Ca(2+) influx were necessary for ERK1/2 activation and nicotine-induced mitogenesis in VSMCs. Downstream to ERK1/2, nicotine induced the phosphorylation of Ets-like gene 1 in a timely co-ordinated manner with the up-regulation of the atherogenic transcription factor, early growth response 1 (Egr-1). The treatment of balloon-injured arteries with a lentivirus vector carrying a short hairpin RNA against Egr-1 abolished the deleterious effect of nicotine on vascular remodelling.
Conclusion:
Nicotine acts through its receptors in VSMC to activate the ERK-Egr-1 signaling cascade that induces cell proliferation and exacerbates post-injury neointimal development.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Administration, Oral
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Animals
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Atherosclerosis / chemically induced*
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Atherosclerosis / prevention & control
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Calcium Signaling / drug effects
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Catheterization / adverse effects
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Cell Proliferation / drug effects*
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Cells, Cultured
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Chelating Agents / pharmacology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Early Growth Response Protein 1 / genetics
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Early Growth Response Protein 1 / metabolism*
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Enzyme Activation
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Iliac Artery / drug effects
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Iliac Artery / metabolism
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Iliac Artery / pathology
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Ki-67 Antigen / metabolism
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / injuries
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / metabolism
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Myocytes, Smooth Muscle / pathology
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Nicotine / administration & dosage
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Nicotine / toxicity*
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Nicotinic Agonists / administration & dosage
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Nicotinic Agonists / toxicity*
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Nicotinic Antagonists / pharmacology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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Rats
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Rats, Sprague-Dawley
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Receptors, Nicotinic / drug effects
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Receptors, Nicotinic / metabolism
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Time Factors
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Transfection
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Tunica Intima / drug effects*
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Tunica Intima / injuries
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Tunica Intima / metabolism
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Tunica Intima / pathology
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ets-Domain Protein Elk-1 / metabolism
Substances
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Chelating Agents
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Early Growth Response Protein 1
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Egr1 protein, rat
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Elk1 protein, rat
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Ki-67 Antigen
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Nicotinic Agonists
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Nicotinic Antagonists
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Protein Kinase Inhibitors
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Receptors, Nicotinic
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ets-Domain Protein Elk-1
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Nicotine
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3