Involvement of Yes‐associated protein 1 (YAP1) in doxorubicin‐induced cytotoxicity in H9c2 cardiac cells

Takaguri, Akira; Akihiro, Ohmiya; Sasano, Jun; Satoh, Kumi

doi:10.1002/cbin.11285

Cited by 6 publications

(6 citation statements)

References 30 publications

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“…YAP1 is also associated with T2DM-induced myocardial fibrosis (Liu, et al, 2020) and renal interstitial fibrogenesis (J Chen J. et al, 2020). MST1/2 and LATS1/2 were down-regulated and showed increased phosphorylation levels during cardiomyocyte injury, which inhibited the nuclear translocation of YAP (Liu et al, 2019;Takaguri et al, 2020). Consistent with the above, we found that folic acid inhibited phosphorylation of YAP and LATS during the pyroptosis of H9C2 cells and T2DM mice, underscoring the involvement of the Hippo signaling pathway in T2DM-induced myocardial injury.…”

Section: Discussionsupporting

confidence: 88%

Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells

Hong

Zha

Wang

et al. 2021

Front. Mol. Biosci.

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Diabetic cardiomyopathy (DCM) is the leading cause of death in diabetic patients. Folic acid has a protective effect on diabetes-induced cardiomyocyte damage. The aim of this study was to explore the effects of folic acid on cardiomyocytes cultured under high glucose and fat (HGF) conditions and type 2 diabetes mellitus (T2DM) mice, and elucidate the underlying mechanisms. Bioinformatics analysis was used to identify the potential drugs through the Drug-Gene Interaction database. H9C2 cardiomyocytes were cultured with 30 mM glucose and 500 nM palmitic acid in the presence or absence of folic acid or YAP1 inhibitor (verteporfin) or YAP1 siRNA. The cell viability and lactate dehydrogenase (LDH) release were measured using specific assay kits. Pyroptosis was detected by flow cytometry. The concentrations of IL-1β and IL-18 in the supernatants were measured by ELISA. The NLRP3, ASC and caspase-1 mRNA levels were detected by qRT-PCR and that the proteins expression of NLRP3, ASC, cleaved caspase-1 (p10), caspase-1, YAP1, p-YAP1, LATS1 and P-LATS1 were detected by Western blotting. C57BL/6 mice were fed with high fat diet (HFD) combined with streptozotocin (STZ) intraperitoneally to establish a T2DM model, folic acid or PBS treatment for 8 weeks by oral gavage, blood glucose and body weight were measured every 4 weeks, mouse heart tissue was used to detect pyroptosis and hippo signaling pathway related protein expression. We identified 427 differentially expressed genes in the cardiac tissues of high fat diet + streptozotocin mice, among the 30 most significantly DEGs, folic acid was predicted to be the most likely therapeutic drug. Folic acid alleviated HGF-induced cell damage in vitro and in vivo by decreasing activation of the Hippo pathway, as indicated by lower LDH release and increased cell viability, and decreased expression of NLRP3, ASC, cleaved caspase-1, IL-1β, IL-18, p-YAP and p-LATS. Verteporfin or YAP1 siRNA neutralized the protective effect of folic acid by reversing YAP1-induced pyroptosis. Folic acid reduced NLRP3 inflammasome-mediated pyroptosis by down-regulating the Hippo signaling pathway, thereby effectively reducing T2DM-induced damage in H9C2 cells and animals.

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Section: Discussionsupporting

confidence: 88%

Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells

Hong

Zha

Wang

et al. 2021

Front. Mol. Biosci.

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“… 14 Moreover, when YAP is overexpressed in the adult mouse heart, enhanced preservation of heart function and reduced scar size was observed after myocardial infarction. 13 Consistent with the in vivo observation of doxorubicin‐induced reduction of heart size in mice, 15 doxorubicin treatment decreased the expression of YAP and caused cell death of neonatal and H9c2 rat cardiomyocytes in vitro . 16 , 17 In contrast, overexpression of YAP inhibited doxorubicin‐induced cardiomyocyte in vitro .…”

Section: Introductionsupporting

confidence: 76%

“…YAP/TAZ nuclear translocation (and mRNA levels) was also increased, most likely due to doxorubicin‐induced cell loss and subsequent lower cell density, corresponding with the mechanotransducer role of YAP/TAZ activated by altered extracellular and cell–cell connections. 15 , 19 We showed that overexpression of YAP improved doxorubicin‐induced cell death markers such as cell loss and reduction in mitochondrial membrane potential; moreover, YAP overexpression increased cell proliferation, suggesting that increasing YAP expression may be a beneficial strategy against doxorubicin‐induced cardiotoxicity. Given that increased YAP might lead to drug resistance in cancer cells, 36 , 37 it is important to consider cardio‐selective overexpression when developing new cardioprotective strategies.…”

Section: Discussionmentioning

confidence: 89%

“…The Hippo pathway and YAP/TAZ transcriptional co‐activators in cardiotoxicity have previously been characterized in H9c2 rat cardiac cells and animal models. 15 , 18 , 19 However, there has been no human‐based study investigating YAP/TAZ transcriptional co‐activators in doxorubicin‐induced cardiotoxicity. In this study, we analysed ex vivo human heart samples to evaluate key signalling pathways in doxorubicin‐induced cardiac cell death.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy

et al. 2021

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Aims Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation, and stem cell self‐renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress‐related and cell death‐related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co‐activators of Hippo signalling, YAP and TAZ, in human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. Methods and results RNA‐sequencing analysis of human heart samples with doxorubicin‐induced end‐stage heart failure and healthy controls showed that YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin on hiPSC‐CMs in vitro. Using an automated high‐content screen of 96 clinically relevant antineoplastic and cardiotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC‐CMs and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin‐induced cell loss in hiPSC‐CMs by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. hiPSC‐CM calcium transients did not change in response to YAP/TAZ silencing. Conclusions Our results suggest that Hippo signalling is involved in clinical anthracycline‐induced cardiomyopathy. Modelling with hiPSC‐CMs in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin‐induced cardiotoxicity.

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“…By contrast, activation of the Hippo Pathway (STK3/STK4 kinase activity) and the subsequent inhibition or degradation of YAP1 increases oxidative stress and cell death in cardiac cells [25]. Several studies have further shown that YAP1 activation counteracts doxorubicin-induced cardiomyopathy in vitro and ex vivo [26,27]. However, transcription factors such as YAP1 are notoriously difficult to modulate directly with small-molecule compounds [28].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Divergent Roles of STK3 Inhibits Breast Cancer Cell Growth and Opposes Doxorubicin-Induced Cardiotoxicity In Vitro

Nam

Schirmer

Loh

et al. 2023

Cancers

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Breast cancer (BCa) is the most prevalent type of cancer in women. Several therapies used in the treatment of breast cancer are associated with clinically important rates of cardiovascular toxicity during or after treatment exposure, including anthracyclines. There is a need for new BCa therapeutics and treatments that mitigate chemotherapy-induced cardiotoxicity in BCa. In this study, we examine the effects of Serine/Threonine Kinase 3 (STK3) inhibition in the context of BCa therapy and cardioprotection from doxorubicin. STK3 (also known as MST2) is a key member of the Hippo Tumor-Suppressor Pathway, which regulates cell growth and proliferation by inhibiting YAP/TAZ co-transcription factors. Canonically, STK3 should restrict BCa growth; however, we observed that STK3 is amplified in BCa and associated with worse patient outcomes, suggesting a noncanonical pro-tumorigenic role. We found BCa cell lines have varying dependence on STK3. SUM52PE cells had the highest expression and dependence on STK3 in genetic and pharmacological assays. MCF-7 and MDA-MB-231 were less sensitive to STK3 targeting in standard proliferation assays, but were STK3 dependent in colony formation and matrigel invasion assays. In contrast, STK3 inhibition mitigated the toxic effects of doxorubicin in H9C2 rat cardiomyocytes by increasing YAP expression. Importantly, STK3 inhibition in BCa cells did not interfere with the therapeutic effects of doxorubicin. Our studies highlight STK3 is a potential molecular target for BCa with dual therapeutic effects: suppression of BCa growth and progression, and chemoprotection in cardiomyocytes.

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Involvement of Yes‐associated protein 1 (YAP1) in doxorubicin‐induced cytotoxicity in H9c2 cardiac cells

Cited by 6 publications

References 30 publications

Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells

Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells

Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy

Targeting the Divergent Roles of STK3 Inhibits Breast Cancer Cell Growth and Opposes Doxorubicin-Induced Cardiotoxicity In Vitro

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