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

Tünde Berecz; Angela Yiu; Orsolya Vittay; Barbara Orsolits; Maxime Mioulane; Cristobal G Dos Remedios; Robin Ketteler; Bela Merkely; Ágota Apáti; Sian E Harding; Nicola Hellen; Gabor Foldes

doi:10.1002/ehf2.13756

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

ESC Heart Fail. 2022 Feb;9(1):224-235. doi: 10.1002/ehf2.13756. Epub 2021 Dec 21.

Authors

Tünde Berecz^{1

2}, Angela Yiu³, Orsolya Vittay⁴, Barbara Orsolits¹, Maxime Mioulane⁴, Cristobal G Dos Remedios^{5

6}, Robin Ketteler⁷, Bela Merkely¹, Ágota Apáti², Sian E Harding⁴, Nicola Hellen⁴, Gabor Foldes^{1

4}

Affiliations

¹ Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, Budapest, H1122, Hungary.
² Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary.
³ Department of Surgery and Cancer, Imperial College London, London, UK.
⁴ National Heart and Lung Institute, Imperial College London, London, UK.
⁵ Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
⁶ Bosch Institute, The University of Sydney, Sydney, NSW, Australia.
⁷ Laboratory for Molecular Cell Biology, University College London, London, UK.

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.

Keywords: Doxorubicin-induced cardiotoxicity; Hippo signalling; Human pluripotent stem cell-derived cardiomyocytes; YAP/TAZ.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathies* / chemically induced
Cardiomyopathies* / metabolism
Cardiotoxicity / etiology
Doxorubicin / adverse effects
Doxorubicin / metabolism
Humans
Myocytes, Cardiac / metabolism
Transcription Factors* / genetics
Transcription Factors* / metabolism
Transcription Factors* / pharmacology
YAP-Signaling Proteins

Substances

Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Doxorubicin

Abstract

Publication types

MeSH terms

Substances

Grants and funding