title: Novel role of Egr-1 in nicotine-related neointimal formation.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB 7147A, Miami, FL 33136, USA.
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Vazquez-Padron
authors.forename: Dania
authors.initials: D
authors.lastname: Mateu
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez-Menocal
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wei
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
authors.forename: Si M
authors.initials: SM
authors.lastname: Pham
mesh_terms: D000284:Administration, Oral; D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020013:Calcium Signaling / Q000187:drug effects; D002404:Catheterization / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D007083:Iliac Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000008:administration & dosage / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C494114:Elk1 protein, rat; D019394:Ki-67 Antigen; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D047428:Protein Kinase Inhibitors; D011978:Receptors, Nicotinic; D050807:ets-Domain Protein Elk-1; D009538:Nicotine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3