Open AccessTranscriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy
Author(s) -
Berecz Tünde,
Yiu Angela,
Vittay Orsolya,
Orsolits Barbara,
Mioulane Maxime,
Remedios Cristobal G.,
Ketteler Robin,
Merkely Bela,
Apáti Ágota,
Harding Sian E.,
Hellen Nicola,
Foldes Gabor
Publication year - 2022
Publication title -
esc heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.787
H-Index - 25
ISSN - 2055-5822
DOI - 10.1002/ehf2.13756
Subject(s) - hippo signaling pathway , doxorubicin , gene silencing , microbiology and biotechnology , yap1 , cancer research , cell growth , biology , small interfering rna , apoptosis , programmed cell death , transcription factor , signal transduction , cell culture , transfection , biochemistry , gene , chemotherapy , genetics
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.