Berecz, T;
Yiu, A;
Vittay, O;
Orsolits, B;
Mioulane, M;
dos Remedios, CG;
Ketteler, R;
... Foldes, G; + view all
(2021)
Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy.
ESC Heart Failure
10.1002/ehf2.13756.
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ESC Heart Failure - 2021 - Berecz - Transcriptional co‐activators YAP1 TAZ of Hippo signalling in doxorubicin‐induced.pdf - Published Version Download (1MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/ehf2.13756 |
| Publisher version: | https://doi.org/10.1002/ehf2.13756 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, Hippo signalling, YAP/TAZ, Human pluripotent stem cell-derived cardiomyocytes, Doxorubicin-induced cardiotoxicity, CELL-DERIVED CARDIOMYOCYTES, YES-ASSOCIATED PROTEIN, INDUCED CARDIOTOXICITY, PATHWAY, TAZ, YAP, REGENERATION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10141405 |
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