title: Nicotine exposure alters human vascular smooth muscle cell phenotype from a contractile to a synthetic type.
abstract: OBJECTIVE
  Cigarette smoking is a known risk factor for arteriosclerosis. In atheromatous plaques, vascular smooth muscle cells (VSMCs) display a phenotype that is different from the contractile type under normal conditions. Nicotine is the major pharmacological agent in cigarette smoke. However, any direct effect of nicotine on VSMCs remains uncertain. Because nicotine promotes VSMC migration, its phenotype may change due to nicotine.
  
  
  RESULTS
  We used human aorta primary smooth muscle cells (HuAoSMCs), differentiated with transforming growth factor-β, to investigate changes in the protein levels of differentiation markers and in the activity of mitogen-activated protein kinases (MAPKs) after exposure to 0.1 μM of nicotine for 48 h. After nicotine exposure, the protein levels of myosin II 10 (2.93-fold) and β-actin (1.66-fold), synthetic type markers, were increased. In contrast, the levels of the contractile type markers, myosin II 11 (0.63-fold), high-molecular-weight caldesmon (0.40-fold) and SM22 (0.66-fold), which concern differentiated VSMC, were decreased. Moreover, nicotine exposure induced enhanced activation of p38 MAPK (1.30-fold) and extracellular signal-regulated kinase (1.91-fold). These results indicated that the phenotype of HuAoSMCs had changed to a synthetic-like type because of nicotine exposure. Thus, nicotine is one factor that can alter protein expression of differentiation markers in VSMCs. Besides, the increase of intracellular Ca(2+) levels suggested that these effects of nicotine were mediated through nicotinic acetylcholine receptors.
  
  
  CONCLUSIONS
  Nicotine has already been reported to promote VSMC migration from the tunica media to atheromatous plaques in the vascular intima. This phenomenon may occur because nicotine directly induces VSMC transformation from contractile type to synthetic-like type via nicotinic acetylcholine receptors and G protein-coupled receptors.
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yoshiyama
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Bioresources, Mie University, Kamihama-Machuya 1515, Tsu, Mie 514-8507, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Okagaki
authors.affiliation: Research Institute of Pharmaceutical Sciences, Musashino University, Nushitokyo, Tokyo 202-8585, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kohama
authors.affiliation: Department of Health and Nutrition, Takasaki University of Health and Welfare, Takasaki, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Nasu-Kawaharada
authors.affiliation: Department of Biochemistry, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Biochemistry, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Ohshima
authors.affiliation: Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8511, Japan. Electronic address: gacho@gunma-u.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Nakamura
mesh_terms: D001011:Aorta / Q000166:cytology* / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000737:chemistry; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D006801:Humans; D020935:MAP Kinase Signaling System; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009538:Nicotine / Q000008:administration & dosage* / Q000737:chemistry; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D017540:Tunica Media / Q000473:pathology
chemical_list: D002148:Calmodulin-Binding Proteins; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D016212:Transforming Growth Factor beta; D009538:Nicotine; D004247:DNA; D002118:Calcium
keywords: Atherosclerosis; Contractile type; Nicotine; Synthetic type; Vascular smooth muscle