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

ESC Heart Failure

Angela Yiu¹  Bela Merkely²  Tünde Berecz²  Gabor Foldes²  Barbara Orsolits²  Ágota Apáti³  Robin Ketteler⁴  Nicola Hellen⁵  Orsolya Vittay⁵  Sian E. Harding⁵  Maxime Mioulane⁵  Cristobal G. dosRemedios⁶ 

[1] Department of Surgery and Cancer Imperial College London London UK;Heart and Vascular Center Semmelweis University 68 Városmajor Street Budapest H1122 Hungary;Institute of Enzymology, Research Centre for Natural Sciences Eötvös Loránd Research Network Budapest Hungary;Laboratory for Molecular Cell Biology University College London London UK;National Heart and Lung Institute Imperial College London London UK;Victor Chang Cardiac Research Institute Darlinghurst NSW Australia;

关键词: Hippo signalling;    YAP/TAZ;    Human pluripotent stem cell‐derived cardiomyocytes;    Doxorubicin‐induced cardiotoxicity;   

DOI  :  10.1002/ehf2.13756

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown