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      WWC3 inhibits intimal proliferation following vascular injury via the Hippo signaling pathway

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          Abstract

          The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on vascular smooth muscle cells (VSMCs) following injury were investigated, in addition to the associated mechanisms underlying this process. Platelet-derived growth factor BB (PDGF-BB) was used as a cell injury factor, and rats with balloon injuries were used as a model of carotid intimal injury. Furthermore, the expression levels of WWC3 in VSMCs and arteries post-injury were investigated, in addition to the effect of WWC3 on the proliferation and migration of VSMCs. The results demonstrated that following injury, WWC3 expression was suppressed in VSMCs and the rat carotid artery, and the activity of the Hippo signaling pathway was significantly downregulated. In addition, the expression of YY1-associated protein-1 (YAP) and a number of its downstream target genes, including connective tissue growth factor (CTGF), were enhanced, thus enhancing the proliferation and migration of VSMCs. Knockdown of WWC3 suppressed the levels of large tumor suppressor kinase 1 (LATS1) expression and YAP phosphorylation, and the expression of YAP, CTGF and cyclin E was subsequently enhanced, thus promoting cell proliferation and migration. Similar results were obtained following overexpression of WWC3. Treatment with PDGF-BB was revealed to suppress the proliferation and migration of VSMCs transfected with the WWC3 plasmid, compared with VSMCs transfected with an empty vector. The present study demonstrated that WWC3 may interact with LATS1 in order to upregulate the Hippo signaling pathway via co-immunoprecipitation and enhancement of the phosphorylation of LATS1, in addition to the corresponding suppression of the nuclear import of YAP. However, VSMCs transfected with WWC3 plasmid with a deletion of the WW domain fail to exhibit this effect. These results suggested that WWC3 expression is downregulated in VSMCs during neointimal hyperplasia following injury (PDGF-BB stimulation or balloon injury). WWC3 upregulates the activity of the Hippo signaling pathway, and weakens the proliferation and migration of VSMCs. Furthermore, the results of the present study suggested that WWC3 may interact with LATS1 to promote the phosphorylation of YAP and reduce its nuclear translocation, upregulate the activity of the Hippo pathway, and suppress the proliferation and migration of VSMCs following injury.

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          Most cited references20

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          The Hippo signaling pathway in stem cell biology and cancer.

          The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G-protein-coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer.
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            The Hippo-YAP pathway: new connections between regulation of organ size and cancer.

            The control of organ size is a basic biological question. In the past several years, the Hippo signaling pathway has been delineated and shown to be crucial in control of organ size in both Drosophila and mammals. Acting downstream of the Hippo pathway is the Yki/YAP/TAZ transcription co-activators. In mammalian cells, the Hippo pathway kinase cascade inhibits YAP and its paralog TAZ by phosphorylation and promotion of their cytoplasmic localization. The TEAD family transcription factors have recently been identified as evolutionarily conserved key mediators of YAP biological functions. yap is a candidate oncogene, and several other components of the Hippo pathway are tumor suppressors. Dysregulation of the Hippo pathway contributes to the loss of contact inhibition observed in cancer cells. Therefore, the Hippo-YAP pathway connects the regulation of organ size and tumorigenesis.
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              Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65.

              YAP is a multifunctional adapter protein and transcriptional coactivator with several binding partners well described in vitro and in cell culture. To explore in vivo requirements for YAP, we generated mice carrying a targeted disruption of the Yap gene. Homozygosity for the Yap(tm1Smil) allele (Yap-/-) caused developmental arrest around E8.5. Phenotypic characterization revealed a requirement for YAP in yolk sac vasculogenesis. Yolk sac endothelial and erythrocyte precursors were specified as shown by histology, PECAM1 immunostaining, and alpha globin expression. Nonetheless, development of an organized yolk sac vascular plexus failed in Yap-/- embryos. In striking contrast, vasculogenesis proceeded in both the allantois and the embryo proper. Mutant embryos showed patterned gene expression domains along the anteroposterior neuraxis, midline, and streak/tailbud. Despite this evidence of proper patterning and tissue specification, Yap-/- embryos showed developmental perturbations that included a notably shortened body axis, convoluted anterior neuroepithelium, caudal dysgenesis, and failure of chorioallantoic fusion. These results reveal a vital requirement for YAP in the developmental processes of yolk sac vasculogenesis, chorioallantoic attachment, and embryonic axis elongation.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                April 2018
                25 January 2018
                25 January 2018
                : 17
                : 4
                : 5175-5183
                Affiliations
                Department of Cardiology, The First Affiliated Hospital of The China Medical University, Shenyang, Liaoning 110001, P.R. China
                Author notes
                Correspondence to: Professor Guinan Liu, Department of Cardiology, The First Affiliated Hospital of The China Medical University, 155 Nanjing North Street, Shenyang, Liaoning 110001, P.R. China, E-mail: guinanliu@ 123456hotmail.com
                Article
                mmr-17-04-5175
                10.3892/mmr.2018.8484
                5865984
                29393412
                cb11e702-db45-43a1-894c-ec515623e388
                Copyright: © Chen et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 17 December 2016
                : 28 November 2017
                Categories
                Articles

                ww domain-containing protein-3,hippo signaling pathway,smooth muscle cells,vascular injury

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