title: Magnolol attenuates neointima formation by inducing cell cycle arrest via inhibition of ERK1/2 and NF-kappaB activation in vascular smooth muscle cells.
abstract: BACKGROUND
  Endovascular injury induces switching of contractile phenotype of vascular smooth muscle cells (VSMCs) to synthetic phenotype, thereby causing proliferation of VSMCs leading to intimal thickening. The purpose of this study was to assess the effect of magnolol on the proliferation of VSMCs in vitro and neointima formation in vivo, as well as the related cell signaling mechanisms.
  
  
  METHODS
  Tumor necrosis factor alpha (TNF-alpha) induced proliferation ofVSMCs was assessed using colorimetric assay. Cell cycle progression and mRNA expression of cell cycle associated molecules were determined by flow cytometry and reverse transcription polymerase chain reaction (RT-PCR) respectively. The signaling molecules such as ERK1/2,JNK, P38 and NF-kappaB were determined by Western blot analysis. In addition, rat carotid artery balloon injury model was performed to assess the effect of magnolol on neointima formation in vivo.
  
  
  RESULTS
  Oral administration of magnolol significantly inhibited intimal area and intimal/medial ratio (I/M). Our in vitro assays revealed magnolol dose dependently induced cell cycle arrest at G0/G1. Also, magnolol inhibited mRNA and protein expression of cyclin D1, cyclin E, CDK4 and CDK2 in vitro and in vivo. The cell cycle arrest was associated with inhibition of ERK1/2 phosphorylation and NF-kappaB translocation.
  
  
  CONCLUSIONS
  Magnolol suppressed proliferation of VSMCs in vitro and attenuated neointima formation in vivo by inducing cell cycle arrest at G0/G1 through modulation of cyclin D1, cyclin E, CDK4 and CDK2 expression.
  
  
  CONCLUSIONS
  Thus, the results suggest that magnolol could be a potential therapeutic candidate for the prevention of restenosis and atherosclerosis.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Karki
authors.forename: Oak-Min
authors.initials: OM
authors.lastname: Ho
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D017705:Lignans / Q000008:administration & dosage*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D058426:Neointima / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D017705:Lignans; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C005498:magnolol; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3