Integrative Transcriptomics and Cell Systems Analyses Reveal Protective Pathways Controlled by Igfbp-3 in Anthracycline-Induced Cardiomyocyte Injury

Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents, however their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline-induced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systems-level transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. Overall design: Igfbp-3 was overexpressed or silenced in neonatal rat ventricular myocytes (NRVM) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) by adenovirus or siRNA. In Dox treated conditions, cells were subject to 1uM Dox treatment for 24 hours. 2x150 bp sequencing strategy was adopted and an average of 55.5 million reads for each sample acquired. Raw reads were aligned to the rat (mRatBN7.2) or human (grch38) transcriptome by Salmon using default parameters.