Dataset Information

Proteomics to study cardiotoxic noxae in adults

ABSTRACT: The heart tissue is a potential target of various noxae contributing to the onset of cardiovascular diseases. However, underlying pathophysiological mechanisms are largely unknown. Human stem cell-derived models are promising, but a major concern is the cell immaturity when estimating risks for adults. In this study, 3D aggregates of human embryonic stem cell-derived cardiomyocytes were cultivated for 300 days and characterized regarding degree of maturity, structure, and cell composition. Furthermore, effects of ionizing radiation (X rays, 0.1–2 Gy) on matured aggregates were investigated, representing one of the noxae that are challenging to assess. Video-based functional analyses were correlated to changes in the proteome after the irradiation. Cardiomyocytes reached maximum maturity after 100 days in cultivation, judged by α-actinin lengths, displayed typical multinucleation and branching. At this time, aggregates contained all major cardiac cell types, proven by the patch-clamp technique. Matured and X-ray-irradiated aggregates revealed a subtle increase in beat rates and decrease in rhythmicity in a dose-dependent manner compared to non irradiated sham controls. The proteome analysis provides first insights into signaling mechanisms contributing to cardiotoxicity. Here, we propose an in vitro model suitable to screen various noxae to target adult cardiotoxicity by preserving all benefits of a 3D tissue culture.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Pluripotent Stem Cell

SUBMITTER: Christine von Toerne

LAB HEAD: Insa s. Schroeder

PROVIDER: PXD028099 | Pride | 2021-11-04

REPOSITORIES: Pride

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Publications

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults.

Smit Timo T Schickel Esther E Azimzadeh Omid O von Toerne Christine C Rauh Oliver O Ritter Sylvia S Durante Marco M Schroeder Insa S IS

Cells 20210930 10

The heart tissue is a potential target of various noxae contributing to the onset of cardiovascular diseases. However, underlying pathophysiological mechanisms are largely unknown. Human stem cell-derived models are promising, but a major concern is cell immaturity when estimating risks for adults. In this study, 3D aggregates of human embryonic stem cell-derived cardiomyocytes were cultivated for 300 days and characterized regarding degree of maturity, structure, and cell composition. Furthermo ...[more]

PMID: 34685588

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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

Dataset Information

Proteomics to study cardiotoxic noxae in adults

Publications

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults.

Similar Datasets

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