Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of non-diabetic rat hearts treated with rosiglitazone against vehicle-treated controls

ABSTRACT: Rosiglitazone is an antidiabetic drug associated with controversial cardiovascular effects; however, its molecular impact on healthy myocardium remains insufficiently characterized. Therefore, this experiment aimed to identify rosiglitazone-induced gene expression changes related to cardiotoxicity in non-diabetic rat hearts using a multi-omics approach. The study was designed to support the development of preclinical strategies capable of detecting early molecular signatures associated with drug-induced cardiotoxicity. Male Wistar rats received daily oral rosiglitazone administration for 28 days, followed by sham surgery and tissue collection. Hearts were isolated and perfused using the Langendorff system to remove residual blood before downstream molecular analyses.

INSTRUMENT(S): NextSeq 2000

ORGANISM(S): Rattus norvegicus

SUBMITTER: Márta Szabó

PROVIDER: E-MTAB-17177 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

Project description:1.1Background and PurposeHidden cardiotoxicity is defined as drug-induced cardiotoxicity that becomes obvious only in the presence of comorbidities. However, the molecular mechanisms of hidden cardiotoxicity are not always known. Therefore, unbiased multi-omics approaches could assist in revealing regulatory pathways. The most notable representative of hidden cardiotoxic drugs is the cyclooxygenase-2-inhibitor rofecoxib. We previously reported increased mortality in rats due to proarrhythmic effects of rofecoxib on ischemic hearts. Here, we aimed to identify molecular mechanisms of hidden cardiotoxicity exemplified by rofecoxib that present prior to comorbidities.1.2Experimental Approach and Key ResultsRats were treated with rofecoxib or its vehicle for four weeks. RNA sequencing and proteomic datasets of heart samples were used for differential expression and pathway reconstruction analyses. In this model, mechanisms of hidden cardiotoxicity were unable to be revealed by transcriptomic analyses. However, mass-spectrometry-based proteomics showed conspicuous changes, revealing 132 proteins that were dysregulated in expression or on phosphorylation sites. Importantly, the phospho-proteomics allowed us to identify two kinases that may mediate cardiotoxicity. Finally, pathway reconstruction maps a complex molecular machinery whose clustered proteins regulate processes involving cytoskeleton binding, mRNA processing, proteolysis, translation, citrate acid cycle, and calcium ion signalling.1.3Conclusion and ImplicationsThis is the first demonstration that multi-omics characterization can reveal underlying regulatory pathways of hidden cardiotoxicity. Importantly, our study shows that transcriptomics gives limited information on the hidden cardiotoxic effects of rofecoxib, that are mainly mediated by changes in posttranslational modifications and protein expression. These changes, among other mechanisms, may disturb the cardiac calcium handling, which could explain the fatal arrhythmias following ischemia/reperfusion observed with rofecoxib.

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RNA-seq of non-diabetic rat hearts treated with rosiglitazone against vehicle-treated controls

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