Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy
Abstract 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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-02-01
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| Series: | ESC Heart Failure |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ehf2.13756 |
| _version_ | 1819243246783561728 |
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| author | Tünde Berecz Angela Yiu Orsolya Vittay Barbara Orsolits Maxime Mioulane Cristobal G. dosRemedios Robin Ketteler Bela Merkely Ágota Apáti Sian E. Harding Nicola Hellen Gabor Foldes |
| author_facet | Tünde Berecz Angela Yiu Orsolya Vittay Barbara Orsolits Maxime Mioulane Cristobal G. dosRemedios Robin Ketteler Bela Merkely Ágota Apáti Sian E. Harding Nicola Hellen Gabor Foldes |
| author_sort | Tünde Berecz |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-23T14:52:39Z |
| format | Article |
| id | doaj.art-cfa42de32b8a4c7f89de595f9ce54f50 |
| institution | Directory Open Access Journal |
| issn | 2055-5822 |
| language | English |
| last_indexed | 2024-12-23T14:52:39Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | ESC Heart Failure |
| spelling | doaj.art-cfa42de32b8a4c7f89de595f9ce54f502022-12-21T17:42:54ZengWileyESC Heart Failure2055-58222022-02-019122423510.1002/ehf2.13756Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathyTünde Berecz0Angela Yiu1Orsolya Vittay2Barbara Orsolits3Maxime Mioulane4Cristobal G. dosRemedios5Robin Ketteler6Bela Merkely7Ágota Apáti8Sian E. Harding9Nicola Hellen10Gabor Foldes11Heart and Vascular Center Semmelweis University 68 Városmajor Street Budapest H1122 HungaryDepartment of Surgery and Cancer Imperial College London London UKNational Heart and Lung Institute Imperial College London London UKHeart and Vascular Center Semmelweis University 68 Városmajor Street Budapest H1122 HungaryNational Heart and Lung Institute Imperial College London London UKVictor Chang Cardiac Research Institute Darlinghurst NSW AustraliaLaboratory for Molecular Cell Biology University College London London UKHeart and Vascular Center Semmelweis University 68 Városmajor Street Budapest H1122 HungaryInstitute of Enzymology, Research Centre for Natural Sciences Eötvös Loránd Research Network Budapest HungaryNational Heart and Lung Institute Imperial College London London UKNational Heart and Lung Institute Imperial College London London UKHeart and Vascular Center Semmelweis University 68 Városmajor Street Budapest H1122 HungaryAbstract 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.https://doi.org/10.1002/ehf2.13756Hippo signallingYAP/TAZHuman pluripotent stem cell‐derived cardiomyocytesDoxorubicin‐induced cardiotoxicity |
| spellingShingle | Tünde Berecz Angela Yiu Orsolya Vittay Barbara Orsolits Maxime Mioulane Cristobal G. dosRemedios Robin Ketteler Bela Merkely Ágota Apáti Sian E. Harding Nicola Hellen Gabor Foldes Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy ESC Heart Failure Hippo signalling YAP/TAZ Human pluripotent stem cell‐derived cardiomyocytes Doxorubicin‐induced cardiotoxicity |
| title | Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy |
| title_full | Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy |
| title_fullStr | Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy |
| title_full_unstemmed | Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy |
| title_short | Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy |
| title_sort | transcriptional co activators yap1 taz of hippo signalling in doxorubicin induced cardiomyopathy |
| topic | Hippo signalling YAP/TAZ Human pluripotent stem cell‐derived cardiomyocytes Doxorubicin‐induced cardiotoxicity |
| url | https://doi.org/10.1002/ehf2.13756 |
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