The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP

Tomomi Kimura-Wozniak, Aparna Duggirala, Madeleine C Smith, Stephen J White, Graciela Sala-Newby, Andrew C Newby, Mark Bond

Research output: Contribution to journalArticle (Academic Journal)peer-review

40 Citations (Scopus)
454 Downloads (Pure)

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 and results

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.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume90
Early online date25 Nov 2015
DOIs
Publication statusPublished - Jan 2016

Keywords

  • 3′-5′-cyclic adenosine monophosphate
  • CAMP
  • TAZ
  • Tead
  • VSMC
  • YAP

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