Abstract
Rationale: Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents. Their use however is hindered by the risk of anthracycline-induced cardiotoxicity (AIC). Our understanding of protective pathways activated by cardiomyocytes following AIC remains incomplete. Insulin-like growth factor binding protein (Igfbp)-3, the most abundant Igfbp family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cell types. Whereas Igfbp-3 is significantly induced by Dox in the heart, its role in AIC remains ill-defined. Methods and Results: 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 (iPSC-CMs). Our findings reveal that Dox induces the nuclear enrichment of Igfbp-3 in cardiomyocytes. Furthermore, Igfbp-3 overexpression leads to a significant reduction of γ-H2AX, a marker of DNA damage (56% reduction vs. control, n=3, P<0.05), and impedes topoisomerase (Top)-2β expression which forms a Top2β-Dox-DNA cleavage complex leading to DNA double-strand breaks (44% reduction vs. control, n=3, P<0.01). Next generation sequencing and gene network analyses of iPSC-CMs treated with Dox reveal that Igfbp-3 perturbation modulates genes implicated in microtubule function and cardiomyocyte contraction. Stimulated Emission Depletion (STED) microscopy and immunoblotting further indicate that Igfbp-3 knockdown exacerbates detyrosinated microtubule accumulation (STED, 21% increase vs. control, n=16-19, P<0.05; immunoblotting, 62% increase vs. control, n=6, P<0.01) – a hallmark of increased cardiomyocyte stiffness and heart failure – and favorably affects contractility following Dox treatment. Conclusion: Our delineation of the protective role of Igfbp-3 in AIC provides novel insight into pathways induced by cardiomyocytes to mitigate DNA damage and apoptosis, and improve contractile function.
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