Regulation of Myocardial Cell Growth and Death by the Hippo Pathway

Ikeda, Shohei; Sadoshima, Junichi

doi:10.1253/circj.cj-16-0476

Cited by 57 publications

(54 citation statements)

References 108 publications

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“…Chen et al delineated that the Hippo pathway is activated and is behind the occurrence of adipogenesis in arrhythmogenic cardiomyopathy. Hippo signalling pathway also plays a critical role in cardiac ischaemic injury and MI, where YAP exerts pro‐survival effect on cardiac tissue through interaction with FoxOs, miR‐206 and Akt . Cardiac‐specific YAP heterozygous knockout mice show significant increases in apoptosis after MI .…”

Section: Discussionmentioning

confidence: 99%

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Wang

Park

et al. 2020

J Cellular Molecular Medi

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There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin‐induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL‐positive cells, down‐regulation of anti‐apoptotic protein Bcl‐2, as well as up‐regulation of pro‐apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin‐melatonin co‐treatment alleviated in vivo doxorubicin‐induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down‐regulated Yes‐associated protein (YAP) expression, while YAP levels were maintained under co‐treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin‐treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Wang

Park

et al. 2020

J Cellular Molecular Medi

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“…Considering that the reduction in the nuclear YAP (nYAP) is a sign of YAP inactivation (Ikeda & Sadoshima, ), we determined total YAP as well as nYAP and cytoplasmic YAP (cYAP) by preparing respective protein fractions. GAPDH and Lamin A/C were used as marker proteins to ensure the good separation of the protein fractions (Figure e).…”

Section: Resultsmentioning

confidence: 99%

Stimulation of β‐adrenoceptors up‐regulates cardiac expression of galectin‐3 and BIM through the Hippo signalling pathway

Zhao

Lü

Nguyen

et al. 2019

British J Pharmacology

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Background and Purpose Expression of the pro‐fibrotic galectin‐3 and the pro‐apoptotic BIM is elevated in diseased heart or after β‐adrenoceptor stimulation, but the underlying mechanisms are unclear. This question was addressed in the present study. Experimental Approach Wild‐type mice and mice with cardiac transgenic expression of β 2 ‐adrenoceptors, mammalian sterile‐20 like kinase 1 (Mst1) or dominant‐negative Mst1, and non‐specific galectin‐3 knockout mice were used. Effects of the β‐adrenoceptor agonist isoprenaline or β‐adrenoceptor antagonists were studied. Rat cardiomyoblasts (H9c2) were used for mechanistic exploration. Biochemical assays were performed. Key Results Isoprenaline treatment up‐regulated expression of galectin‐3 and BIM, and this was inhibited by non‐selective or selective β‐adrenoceptor antagonists (by 60–70%). Cardiac expression of galectin‐3 and BIM was increased in β 2 ‐adrenoceptor transgenic mice. Isoprenaline‐induced up‐regulation of galectin‐3 and BIM was attenuated by Mst1 inactivation, but isoprenaline‐induced galectin‐3 expression was exaggerated by transgenic Mst1 activation. Pharmacological or genetic activation of β‐adrenoceptors induced Mst1 expression and yes‐associated protein (YAP) phosphorylation. YAP hyper‐phosphorylation was also evident in Mst1 transgenic hearts with up‐regulated expression of galectin‐3 (40‐fold) and BIM as well as up‐regulation of many YAP‐target genes by RNA sequencing. In H9c2 cells, isoprenaline induced YAP phosphorylation and expression of galectin‐3 and BIM, effects simulated by forskolin but abolished by PKA inhibitors, and YAP knockdown induced expression of galectin‐3 and BIM. Conclusions and Implications Stimulation of cardiac β‐adrenoceptors activated the Mst1/Hippo pathway leading to YAP hyper‐phosphorylation with enhanced expression of galectin‐3 and BIM. This signalling pathway would have therapeutic potential. 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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“…The core of this pathway is Mst/large tumour suppressor homologue (Lats) forming a kinase cascade that regulates activity of the down-stream transcription co-regulator yes-activated protein (YAP) and its paralogue transcriptional co-activator with PDZ-binding motif (TAZ). YAP/TAZ forms the main signal output of the Hippo pathway through binding to numerous transcription factors and epigenetic factors to regulate expression of a range of target genes thereby promoting cell proliferation and survival (Ikeda & Sadoshima, 2016;Plouffe, Hong, & Guan, 2015;Yu et al, 2015). Matsuda et al, 2016;Meng et al, 2018;Plouffe et al, 2016;Yu et al, 2015).…”

Section: The β-Adrenoceptor-hippo Pathway Regulates Gal-3 Expressionmentioning

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%

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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Regulation of Myocardial Cell Growth and Death by the Hippo Pathway

Cited by 57 publications

References 108 publications

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

Stimulation of β‐adrenoceptors up‐regulates cardiac expression of galectin‐3 and BIM through the Hippo signalling pathway

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

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