Abstract
AimsHippo 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 resultsRNA‐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.ConclusionsOur 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.
Highlights
Traditional chemotherapeutic drug families, like anthracyclines, are highly effective drugs, against breast cancer and haematological malignancies.[1,2] these drugs are the leading cause of cardiac dysfunction in cancer survivors.[3]
Overexpression of yes-associated protein (YAP) inhibited doxorubicin-induced cardiomyocyte in vitro.[17]. These findings suggest that YAP/transcriptional co-activator with PDZ-binding motif (TAZ) activation is modified in response to doxorubicin treatment and is a promising potential target for regenerative or protective therapy of the heart.[18]
Screening of biopsies has shown that high nuclear translocation and expression of YAP/TAZ is associated with a poor prognosis and reduced survival rate in various cancers.[23,24,25,26]
Summary
Traditional chemotherapeutic drug families, like anthracyclines, are highly effective drugs, against breast cancer and haematological malignancies.[1,2] these drugs are the leading cause of cardiac dysfunction in cancer survivors.[3]. It is unknown whether chronic manipulation of YAP/TAZ signalling has any potentially deleterious effects on cardiovascular function and homeostasis
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