Protein kinase A and the exchange protein directly activated by cAMP (Epac) modulate phenotype plasticity in human airway smooth muscle.
Br J Pharmacol
; 164(3): 958-69, 2011 Oct.
Article
em En
| MEDLINE
| ID: mdl-21426315
ABSTRACT
BACKGROUND AND PURPOSE:
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. EXPERIMENTALAPPROACH:
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. KEYRESULTS:
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 AND IMPLICATIONS 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Traqueia
/
Proteínas Quinases Dependentes de AMP Cíclico
/
Fatores de Troca do Nucleotídeo Guanina
/
Músculo Liso
Limite:
Humans
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Holanda