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

Kimura, TE, Duggirala, A, Smith, MC, White, S, Sala-Newby, GB, Newby, AC and Bond, M (2016) The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP. Journal of Molecular and Cellular Cardiology, 90. pp. 1-10. ISSN 0022-2828

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Official URL: http://www.elsevier.com/locate/issn/00222828

Abstract

© 2015 The Authors. 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.

Item Type:	Article
Peer-reviewed:	Yes
Date Deposited:	09 Jun 2017 08:56
Publisher:	Elsevier
Additional Information:	This is an Open Access article published in Journal of Molecular and Cellular Cardiology, published by Elsevier, copyright The Author(s).
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cell Biology, Cardiovascular System & Cardiology, YAP, TAZ, TEAD, cAMP, 3 '-5 '-Cyclic adenosine monophosphate, VSMC, CYCLIN D1 EXPRESSION, NEOINTIMA FORMATION, CONTACT INHIBITION, SIGNALING PATHWAY, BALLOON INJURY, GROWTH-CONTROL, NITRIC-OXIDE, VEIN GRAFTS, IN-VITRO, MIGRATION, Muscle, Smooth, Myocytes, Smooth Muscle, Animals, Humans, Rats, Rats, Sprague-Dawley, Amides, Pyridines, Epoprostenol, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-myc, Cyclic AMP, Bucladesine, Signal Transduction, Cell Proliferation, Gene Expression Regulation, Male, Apoptosis Regulatory Proteins, Transforming Growth Factor beta2, Thiazolidines, rho-Associated Kinases, Connective Tissue Growth Factor, Cysteine-Rich Protein 61, Primary Cell Culture, Colforsin, Bridged Bicyclo Compounds, Heterocyclic, 3′-5′-Cyclic adenosine monophosphate, TAZ, TEAD, VSMC, YAP, cAMP, Amides, Animals, Apoptosis Regulatory Proteins, Bridged Bicyclo Compounds, Heterocyclic, Bucladesine, Cell Proliferation, Colforsin, Connective Tissue Growth Factor, Cyclic AMP, Cysteine-Rich Protein 61, Epoprostenol, Gene Expression Regulation, Humans, Intracellular Signaling Peptides and Proteins, Male, Muscle, Smooth, Myocytes, Smooth Muscle, Primary Cell Culture, Proto-Oncogene Proteins c-myc, Pyridines, Rats, Rats, Sprague-Dawley, Signal Transduction, Thiazolidines, Transforming Growth Factor beta2, rho-Associated Kinases, 1102 Cardiovascular Medicine And Haematology, Cardiovascular System & Hematology
URI:	https://e-space.mmu.ac.uk/id/eprint/618533
DOI:	https://doi.org/10.1016/j.yjmcc.2015.11.024
ISSN	0022-2828

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