title: cAMP-response element-binding protein mediates tumor necrosis factor-alpha-induced vascular smooth muscle cell migration.
abstract: OBJECTIVE
  Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions such as atherosclerosis and restenosis after angioplasty. Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is a potent migration factor for VSMCs. cAMP-response element-binding protein (CREB) is the stimulus-induced transcription factor and activates transcription of target genes such as c-fos and interleukin-6. We examined whether CREB is involved in TNF-alpha-induced VSMC migration.
  
  
  RESULTS
  TNF-alpha induced CREB phosphorylation with a peak at 15 minutes of stimulation. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNF-alpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of dominant-negative form of CREB suppressed TNF-alpha-induced CREB phosphorylation and c-fos mRNA expression. VSMC migration was evaluated using a Boyden chamber. Overexpression of dominant-negative form of CREB suppressed VSMC migration as well as Rac1 expression induced by TNF-alpha. Overexpression of dominant-negative Rac1 also inhibited TNF-alpha-induced VSMC migration.
  
  
  CONCLUSIONS
  Our results suggest that p38-MAPK/CREB/Rac1 pathway plays a critical role in TNF-alpha-induced VSMC migration and may be a novel therapeutic target for vascular stenotic lesion. Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions. TNF-alpha, a potent migration factor for VSMCs, activated CREB through p38 mitogen-activated protein kinase (p38-MAPK). CREB inhibition suppressed TNF-alpha-induced VSMC migration and Rac1 expression. These results suggest p38-MAPK/CREB/Rac1 pathway mediates TNF-alpha-induced VSMC migration.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ono
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.forename: Kae
authors.initials: K
authors.lastname: Fukuyama
authors.forename: Naoko
authors.initials: N
authors.lastname: Iino
authors.forename: Satoko
authors.initials: S
authors.lastname: Masuda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D050882:CREB-Binding Protein; D002465:Cell Movement; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology; D005799:Genes, Dominant; D016762:Genes, fos; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology
chemical_list: D007093:Imidazoles; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D010768:Phosphoserine; D005576:Colforsin; D015759:Ionomycin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; C093642:SB 203580