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. 2017 Aug 17;7:8603. doi: 10.1038/s41598-017-09152-x

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© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Notch Pathway Related Genes Following Doxorubicin Treatment. Key events involved in activation of the Notch pathway, implicated in cardiomyocyte proliferation and differentiation. Upon binding of ligands by a signal-sending cell, the Notch receptor gets ‘pulled’ and undergoes a conformational change. This exposes the receptor to a first proteolytic cleavage by ADAM17. Subsequently, further conformational change permits a second proteolytic cleavage by γ-secretase. This is followed by nuclear translocation of the remaining Notch intracellular domain (NICD) which leads to cooperative assembly with the transcription factor CSL and transcriptional co-activator MAML to form a transcriptional activation complex. (B) Zebrafish heart mRNA levels of Notch pathway related genes were determined following doxorubicin or control vehicle injection at days 3, 30, and 60 (n = 5 per condition and per time-point). There was an initial decrease of Notch pathway genes at day 3 following doxorubicin treatment, corresponding to cardiomyocyte death by activation of both apoptosis and necrosis. Thereafter, we observed increased expression of Notch pathway related genes in the doxorubicin treated group with statistical significance in the Notch ligand JAG1 and downstream effector Hey2 at day 30 and day 60 and in DLL4 at day 60. *P < 0.05, **P < 0.01. ADAM17: a disintegrin and metalloproteinase 17. CSL: CBF1, suppressor of hairless, lag-1. DLL4: delta-like ligand 4. HEY: hes related family bHLH transcription factor with YRPW motif. JAG: jagged. MAML: mastermind-like. NICD: Notch intracellular domain. NRG1: neuregulin 1.