The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.
|Authors||Tomomi E. Kimura, Duggirala, A., Madeleine C. Smith, Stephen White, Graciela B. Sala-Newby, Andrew C. Newby and Mark Bond|
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.
|Keywords||3'-5'-Cyclic adenosine monophosphate; CAMP; TAZ; TEAD; VSMC; YAP|
|Journal||Journal of molecular and cellular cardiology|
|Journal citation||Vol 90 (January 2016), pp. 1-10|
|Digital Object Identifier (DOI)||https://doi.org/10.1016/j.yjmcc.2015.11.024|
|Web address (URL)||https://europepmc.org/articles/PMC4727789|
|Online||25 Nov 2015|
|Online||01 Jan 2016|
|Publication process dates|
|Accepted||20 Nov 2015|
|Deposited||08 Jun 2023|
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