Author:
Liu Qing,Wu Haodi,Luo Qing-Jun,Jiang Chao,Duren Zhana,Van Bortle Kevin,Zhao Ming-tao,Zhao Bingqing,Liu Jun,Marciano David P,Lee-McMullen Brittany,Zhu Chenchen,Narasimha Anil M,Gruber Joshua J,Lipchik Andrew M,Guo Hongchao,Watson Nathaniel K,Tsai Ming-Shian,Furihata Takaaki,Tian Lei,Wei Eric,Li Yingxin,Steinmetz Lars M,Wong Wing Hung,Kay Mark A.,Wu Joseph C,Snyder Michael P
Abstract
SUMMARYMaternal drug exposure during pregnancy increases the risks of developmental cardiotoxicity, leading to congenital heart defects (CHDs). In this study, we used human stem cells as an in-vitro system to interrogate the mechanisms underlying drug-induced toxicity during cardiomyocyte differentiation, including anticancer tyrosine kinase inhibitor (TKI) drugs (imatinib, sunitinib, and vandetanib). H1-ESCs were treated with these drugs at sublethal levels during cardiomyocyte differentiation. We found that early exposure to TKIs during differentiation induced obvious toxic effects in differentiated cardiomyocytes, including disarranged sarcomere structure, interrupted Ca2+-handling, and impaired mitochondrial function. As sunitinib exposure showed the most significant developmental cardiotoxicity of all TKIs, we further examine its effect with in-vivo experiments. Maternal sunitinib exposure caused fetal death, bioaccumulation, and histopathologic changes in the neonatal mice. Integrative analysis of both transcriptomic and chromatin accessibility landscapes revealed that TKI-exposure altered GATA4-mediated regulatory network, which included key mitochondrial genes. Overexpression of GATA4 with CRISPR-activation restored morphologies, contraction, and mitochondria function in cardiomyocytes upon TKI exposure early during differentiation. Altogether, our study identified a novel crosstalk mechanism between GATA4 activity and mitochondrial function during cardiomyocyte differentiation, and revealed potential therapeutic approaches for reducing TKI-induced developmental cardiotoxicity for human health.HighlightsEarly-stage exposure to TKIs induced cardiotoxicity and mitochondrial dysfunctionGATA4 transcriptional activity is inhibited by TKIsNetwork analysis reveals interactions between GATA4 and mitochondrial genesGATA4-overexpression rescues cardiomyocytes and mitochondria from TKI exposure
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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