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

Abstract

AimsInhibition 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 resultsElevation 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.ConclusionTaken 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.

Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells

“…An elegant study by Wang et al 36 has recently shown that YAP expression is significantly increased after carotid artery injury, and deletion of YAP attenuates injury-induced neointima formation, which represent an early phase of atherosclerosis. In agreement with this finding, a more recent study has shown that YAP and TAZ are essential for smooth muscle cell proliferation which can be inhibited by YAP inhibitor verteporfin as well as agents that elevate intracellular cyclic AMP levels 37 . Our present study found that atheroprotective LF triggered YAP phosphorylation and decrease YAP nuclear expression, consequently decreased the expression of mechanosensory YAP target genes (CTGF and Cyr61 etc) 38, 39 in ECs.…”

“…It can be anticipated that by use of high content screening or high throughput screening of FDA-approved drug library or natural compounds library, more and more novel and specific YAP inhibitors will be developed for treating various human diseases in the future. In terms of the vasculature, emerging evidence suggests that YAP is also critical for cardiovascular development and diseases 36, 37, 47, 54–57 . Whether genetic deletion of YAP in ECs or pharmacological inhibition of YAP activity could prevent the development of atherosclerosis in preclinical settings warrants further studies.…”

The role of transcriptional coactivator TAZ in gliomas

“…C-myc has been reported as the target gene of TAZ and TEAD [17, 25]. We have shown that the expression of C-myc is consistent with the level of TAZ, so TAZ might promote glioma progression through activation of C-myc.…”

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

“…Therefore, in the present study, we tested several doses of verteporfin, which have also been used in previously published articles. 34,35 Before treatment, cells were starved overnight in serum-free Dulbecco's Modified Eagle's Medium (DMEM; Wako Pure Chemical Industries, Osaka, Japan).…”