title: Protein kinase A and the exchange protein directly activated by cAMP (Epac) modulate phenotype plasticity in human airway smooth muscle.
abstract: OBJECTIVE
  Platelet-derived growth factor (PDGF) modulates the airway smooth muscle (ASM) 'contractile' phenotype to a more 'proliferative' phenotype, resulting in increased proliferation and reduced contractility. Such phenotypic modulation may contribute to airway remodelling in asthma. We have previously shown that the cAMP effector molecules, protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) inhibited PDGF-induced phenotypic modulation in bovine ASM. Here, we investigated these mechanisms in human ASM strips and cells.
  
  
  METHODS
  ASM strips were incubated with PDGF in the absence or presence of the activators of Epac (8-pCPT-2'-O-Me-cAMP) or of PKA (6-Bnz-cAMP) for 4 days. Strips were mounted for isometric contraction experiments or analysed for the expression of contractile markers. Cell proliferation was measured and proliferative markers were analysed under similar conditions.
  
  
  RESULTS
  Activation of Epac and PKA prevented PDGF-induced ASM strip hypocontractility, and restored the expression of smooth muscle actin, myosin and calponin, which had been markedly diminished by PDGF. Epac and PKA activation inhibited the PDGF-induced ASM cell proliferation and G(1)/S phase transition and the expression and phosphorylation of cell cycle regulators.
  
  
  CONCLUSIONS
  Epac and PKA maintain a normally contractile ASM phenotype in a mitogenic environment, suggesting that specific activators of Epac and PKA may be beneficial in the treatment of airway remodelling in asthma.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, The Netherlands. s.s.roscioni@med.umcg.nl
authors.forename: Sara S
authors.initials: SS
authors.lastname: Roscioni
authors.forename: Alwin G
authors.initials: AG
authors.lastname: Prins
authors.forename: Carolina R S
authors.initials: CR
authors.lastname: Elzinga
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.forename: Bart G J
authors.initials: BG
authors.lastname: Dekkers
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.forename: Harm
authors.initials: H
authors.lastname: Maarsingh
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000199:Actins / Q000378:metabolism; D056151:Airway Remodeling / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D000096985:Calponins
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D009218:Myosins; D010982:Platelet-Derived Growth Factor; D000096985:Calponins; C116122:RAPGEF3 protein, human