Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation

Maryam Sharifi-Sanjani,Theodore Guy Avolio,Seyed Mehdi Nouraie,Elena Goncharova,Baojun Chang,Imad Al Ghouleh,Dmitry Goncharov,Mohammad Alhamaydeh,Ahasanul Kobir,Mariah Berman,Mark Ross,Jeffrey Baust,Christine S Moravec,Claudette St Croix,Charles F Mctiernan

doi:10.3390/ijms22116164

Abstract

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.

Highlights

Heart disease and subsequent heart failure (HF) is the major cause of death worldwide [1]
We found that Yesassociated protein (Yap) protein levels were significantly elevated when comparing left ventricular (LV) tissues from HF cohorts to controls (Figure 1A,B)
As ERK1/2 signaling is implicated in HF and it induces cell proliferation as well as being mechanistically linked to HIPPO/Yap signaling [34,43,44,45], we investigated the role of ERK1/2 in Yap-dependent cardiac fibroblast signaling

Summary

Introduction

Heart disease and subsequent heart failure (HF) is the major cause of death worldwide [1]. The HIPPO pathway is a growth suppressor signaling pathway that prevents organ overgrowth by inhibiting cell proliferation and inducing differentiation or apoptosis [3]. The key reciprocal downstream effectors of HIPPO are transcriptional co-activators Yesassociated protein (Yap) and Taz, which are positive regulators of cell proliferation and survival [3]. Yap/Taz are negatively regulated by the central HIPPO components, large tumor suppressor 1 (LATS1) and LATS2, via direct phosphorylation, which reduces Yap protein levels by targeting it for degradation [3]. HIPPO pathway is suggested to collaborate with mammalian target of rapamycin (mTOR) in organs and cells and to enhance proliferation, migration and inhibition of cell differentiation [4,5,6,7,8]

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