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Dysregulation of intercellular communication indicates cellular processes controlled by transcription factors involved in doxorubicin-induced long-term cardiotoxicity in cancer survivors

ABSTRACT: Long-term side effects of doxorubicin include cardiotoxicity. Because studying transcriptional network alterations in human heart at early stages of cardiac dysfunction development is not feasible, in the present study, we used circulating microRNAs (miRNAs) to obtain insight into cellular processes in acute lymphoblastic leukemia (ALL) survivors with a history of doxorubicin treatment. We showed that altered miRNA profiles in plasma and circulating extracellular vesicles (EVs) and particularly the distribution of miRNAs between the two compartments in ALL survivors are linked to cellular transcriptomic processes controlled by transcription factors involved in epigenetic regulation, oxidative stress response, senescence, fibrosis, or epithelial-mesenchymal transition (EMT)—a phenomenon involved in organ injury, repair, and remodeling. These alterations could also be linked to cardiac complications and interindividual variability in cardiomyocyte response to doxorubicin. Thus, circulating miRNAs can indicate the possible molecular mechanisms of cardiotoxicity in patients previously exposed to anthracyclines even when there are no apparent clinical signs of heart dysfunction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145176 | GEO | 2023/01/05

REPOSITORIES: GEO

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Project description:To compare expression profiles in the cardiomyocytes with wild type top2b and those with top2b deletion after in vivo treatment of mice with doxorubicin or drug vehicle Doxorubicin is widely used in modern cancer treatments, despite the advent of targeted therapy. However, a dose-dependent cardiotoxicity often limits its clinical use. The prevailing theory hypothesizes that doxorubicin-induced cardiotoxicity is the result of reactive oxygen species (ROS) generation due to redox-cycling of doxorubicin. Here we showed that cardiomyocyte-specific deletion of Topoisomerase II beta (Top2b) markedly reduced DNA double-strand breaks, apoptosis, and functional damages in doxorubicin-treated hearts. To investigate transcriptomic changes after doxorubicin treatment in wild type mouse and mouse with cardiac specific deletion of Top2b, we examined the expression profiles in 4 groups of mice (3/group), ie. wildtype mice with or without doxorubicin treatment and mice with Top2b deletion in the cardiomyocytes with or without doxorubicin treatment. Mice were treated with doxorubicin (25mg/kg, i.p.) or PBS (drug vehicle) for 16 hr or 72 hr. The heart was removed and cardiomyocytes were isolated by using a Langendorff apparatus. After purification, total RNA was extracted from the cardiomyocytes, purified, and used for gene expression analysis. Compared with that in control cardiomyocytes or cardiomyocytes with Top2b deletion, doxorubicin caused a significant expression change in the genome of cardiomyocytes from the wildtype mice. Among the changes, multiple genes encoding mitochondrial structural protein and components of the respiratory chain complexes were down-regulated 72 hr after treatment while multiple genes in the p53 pathway were up-regulated 16 hr after treatment in the wildtype cardiomyocytes. Expression changes were examined in 2 groups of mice (wild type and conditional knockout of top2b in the cardiomyocytes) treated with doxorubicin or PBS for 16 or 72 hours

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Dysregulation of intercellular communication indicates cellular processes controlled by transcription factors involved in doxorubicin-induced long-term cardiotoxicity in cancer survivors

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