The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.
J Mol Cell Cardiol
; 90: 1-10, 2016 Jan.
Article
em En
| MEDLINE
| ID: mdl-26625714
ABSTRACT
AIMS:
Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. METHODS ANDRESULTS:
Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ.CONCLUSION:
Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
AMP Cíclico
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Miócitos de Músculo Liso
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Peptídeos e Proteínas de Sinalização Intracelular
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Proteínas Reguladoras de Apoptose
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Reino Unido