The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration

Wang, Jun; Liu, Shijie; Heallen, Todd R.; Martin, James F.

doi:10.1038/s41569-018-0063-3

Cited by 303 publications

(272 citation statements)

References 156 publications

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“…This possibility has not been addressed in the in vitro studies already mentioned (Dethlefsen et al, 2017;Kim et al, 2013;Yu et al, 2012). For instance, whereas Lats1/2 and YAP activity can be directly regulated bypassing Mst1 (Plouffe et al, 2016;Wang et al, 2018;Yu et al, 2015), it is induces cardiac up-regulation of Mst1 and Gal-3 as well as YAP phosphorylation, which were all dependent on isoprenaline dosage and treatment duration . These in vivo findings were supported by a recent study in cultured rat cardiomyocytes showing that isoprenaline stimulation induced rapid phosphorylation of both Mst1/2 and YAP (Dalal, Connelly, Singh, & Singh, 2018).…”

Section: Figurementioning

confidence: 99%

“…Activation of the sympatho‐β‐adrenergic system is a characteristic feature of heart disease (Cohn et al, ; Kaye et al, ), and an increasing body of research has implicated a role of the Hippo pathway in heart disease (Chen et al, ; Del Re et al, ; Ikeda & Sadoshima, ; Leach et al, ; Plouffe et al, ; Wang, Liu, Heallen, & Martin, ). Thus, it is likely that activation of the β‐adrenoceptor‐Hippo signalling with resultant suppression of YAP activity might contribute to the pathogenesis of heart disease.…”

Section: Activation Of β‐Adrenoceptors Upregulates Gal‐3 Expression Imentioning

confidence: 99%

“…ECM: extracellular matrix; MOB1/2: Mps one binder kinase activator like 1/2; mTORC: mammalian target of rapamycin complex; NF2: neurofibromin 2 (also known as merlin); PCMT1: protein-L-isoaspartate(D-aspartate) O-methyltransferase; PHLPP: PH domain and leucine rich repeat protein phosphatase; RAP2: Ras-related GTPase; RASSF: Ras association domain-containing proteins; RhoA: a small GTPase; Sav1: salvador homologue 1; TAOK: Tao kinase; TEADs: tea domain family members; βor α-AR: βor α-adrenoceptor Recent studies have shown regulation of the Hippo pathway by hormones and membrane receptors including GPCRs (Ikeda & Sadoshima, 2016;Yu et al, 2012Yu et al, , 2015. Coupling of the βadrenoceptors with the Hippo pathway was first proposed by Yu et al (Yu et al, 2012) Activation of the sympatho-β-adrenergic system is a characteristic feature of heart disease (Cohn et al, 1984;Kaye et al, 1994), and an increasing body of research has implicated a role of the Hippo pathway in heart disease (Chen et al, 2014;Del Re et al, 2013;Ikeda & Sadoshima, 2016;Leach et al, 2017;Plouffe et al, 2016;Wang, Liu, Heallen, & Martin, 2018). Thus, it is likely that activation of the β-adrenoceptor-Hippo signalling with resultant suppression of YAP activity might contribute to the pathogenesis of heart disease.…”

Section: Figurementioning

confidence: 99%

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β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

Zhao

Nguyen

et al. 2019

British J Pharmacology

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Myocardial fibrosis is a key histopathological component that drives the progression of heart disease leading to heart failure and constitutes a therapeutic target. Recent preclinical and clinical studies have implicated galectin‐3 (Gal‐3) as a pro‐fibrotic molecule and a biomarker of heart disease and fibrosis. However, our knowledge is poor on the mechanism(s) that determine the blood level or regulate cardiac expression of Gal‐3. Recent studies have demonstrated that enhanced β‐adrenoceptor activity is a determinant of both circulating concentration and cardiac expression of Gal‐3. Pharmacological or transgenic activation of β‐adrenoceptors leads to increased blood levels of Gal‐3 and up‐regulated cardiac Gal‐3 expression, effect that can be reversed with the use of β‐adrenoceptor antagonists. Conversely, Gal‐3 gene deletion confers protection against isoprenaline‐induced cardiotoxicity and fibrogenesis. At the transcription level, β‐adrenoceptor stimulation activates cardiac mammalian sterile‐20‐like kinase 1, a pivotal kinase of the Hippo signalling pathway, which is associated with Gal‐3 up‐regulation. Recent studies have suggested a role for the β‐adrenoceptor‐Hippo signalling pathway in the regulation of cardiac Gal‐3 expression thereby contributing to the onset and progression of heart disease. This implies a therapeutic potential of the suppression of Gal‐3 expression. In this review, we discuss the effects of β‐adrenoceptor activity on Gal‐3 as a biomarker and causative mediator in the setting of heart disease and point out pivotal knowledge gaps. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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Section: Figurementioning

confidence: 99%

Section: Activation Of β‐Adrenoceptors Upregulates Gal‐3 Expression Imentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

Zhao

Nguyen

et al. 2019

British J Pharmacology

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“…Besides, cell proliferation plays a major role in maintaining cardiomyocyte homoeostasis . Though adult cardiomyocyte has lost the ability to entry cell cycle, cardiomyocyte from embryonic and neonatal mammal is capable of proliferating .…”

Section: Discussionmentioning

confidence: 99%

Alteration of calcium signalling in cardiomyocyte induced by simulated microgravity and hypergravity

Liu

Zhong

Zhou³

et al. 2020

Cell Proliferation

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Objectives Cardiac Ca2+ signalling plays an essential role in regulating excitation‐contraction coupling and cardiac remodelling. However, the response of cardiomyocytes to simulated microgravity and hypergravity and the effects on Ca2+ signalling remain unknown. Here, we elucidate the mechanisms underlying the proliferation and remodelling of HL‐1 cardiomyocytes subjected to rotation‐simulated microgravity and 4G hypergravity. Materials and Methods The cardiomyocyte cell line HL‐1 was used in this study. A clinostat and centrifuge were used to study the effects of microgravity and hypergravity, respectively, on cells. Calcium signalling was detected with laser scanning confocal microscopy. Protein and mRNA levels were detected by Western blotting and real‐time PCR, respectively. Wheat germ agglutinin (WGA) staining was used to analyse cell size. Results Our data showed that spontaneous calcium oscillations and cytosolic calcium concentration are both increased in HL‐1 cells after simulated microgravity and 4G hypergravity. Increased cytosolic calcium leads to activation of calmodulin‐dependent protein kinase II/histone deacetylase 4 (CaMKII/HDAC4) signalling and upregulation of the foetal genes ANP and BNP, indicating cardiac remodelling. WGA staining indicated that cell size was decreased following rotation‐simulated microgravity and increased following 4G hypergravity. Moreover, HL‐1 cell proliferation was increased significantly under hypergravity but not rotation‐simulated microgravity. Conclusions Our study demonstrates for the first time that Ca2+/CaMKII/HDAC4 signalling plays a pivotal role in myocardial remodelling under rotation‐simulated microgravity and hypergravity.

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“…18 The connection of YAP with EphA2 signaling is unknown. 18 The connection of YAP with EphA2 signaling is unknown.…”

Section: Epha2 Interacts With Stabilizes and Phosphorylates Yap Proteinmentioning

confidence: 99%

EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

Huang

Yuan

Chen

et al. 2019

Intl Journal of Cancer

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Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin‐producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC.

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The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration

Cited by 303 publications

References 156 publications

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

Alteration of calcium signalling in cardiomyocyte induced by simulated microgravity and hypergravity

EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

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