Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 90, Issue -, Pages 1-10Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.11.024
Keywords
YAP; TAZ; TEAD; cAMP; 3 '-5 '-Cyclic adenosine monophosphate; VSMC
Categories
Funding
- British Heart Foundation [PG/14/82/31126]
- NIHR Bristol BRU in Cardiovascular Medicine
- British Heart Foundation [PG/15/100/31877] Funding Source: researchfish
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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. (C) 2015 The Authors. Published by Elsevier Ltd.
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