Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MiRNA sequencing of rat hearts treated chronically with rofecoxib or its vehicle

ABSTRACT: We reported previously that chronic treatment with the Cyclooxygenase-2 inhibitor, rofecoxib, increased acute mortality in rats exposed to ischemia/reperfusion injury (I/R). This manifestation of hidden cardiotoxicity was attributed to the proarrhythmic effect of the drug on the ischemic heart. However, rofecoxib also had beneficial effects on ischemic injury, manifesting as decreased infarct size. In the present study, we aimed to identify molecular changes caused by chronic rofecoxib treatment in the heart. Rats were treated with 5.12 mg/kg rofecoxib or its vehicle for four weeks. Messenger RNA (mRNA), microRNA (miRNA) deep sequencing data, and proteomic datasets of left ventricular tissue samples were used for an unbiased differential expression analysis followed by in silico molecular network analysis and experimental target validation. Using mass spectrometry and filtering criteria, 26 proteins were identified that exhibited pronounced changes in protein expression or phosphorylation due to chronic rofecoxib treatment. The transcriptomic analysis showed mild alterations in the heart´s mRNA- and miRNA expression. The posttranscriptional regulation of mRNAs by miRNAs did not result in differential protein expression. This is the first demonstration that chronic rofecoxib treatment affects posttranslational modification and expression of several proteins in the heart. These are potential off-target effects that could account for the hidden cardiotoxic and/or cardioprotective effects of rofecoxib.

INSTRUMENT(S): NextSeq 550

ORGANISM(S): Rattus norvegicus

SUBMITTER: Bennet Weber

PROVIDER: E-MTAB-13909 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:After induction of ischemic chronic heart failure (CHF), mice exhibited depression-like behavior, in terms of increased anhedonia, and decreased both exploratory activity and interest in novelty. On histology, ischemic CHF mice showed no alterations in overall cerebral morphology. To further evaluate relevant behavioral changes found in CHF mice, RNA-sequencing analysis of prefrontal cortex and hippocampus - the brain regions, whose structural and functional alterations are associated with an increased risk for developing major depressive disorder - and of left myocardial tissue was performed in CHF vs. sham-operated animals. RNA-sequencing revealed relevant changes in hippocampal or prefrontal cortical expression of genes responsible for axonal vesicle transport (Kif5b), signal transduction (Arc, Gabrb2), limitation of inflammation (RORA; Nr4a1) and of hypoxic brain damage (Hif3a). Besides, the actual literature describes some of the genes (RORA, Gabrb2, Npas4, and Junb) being associated with depression-like behavior. Nr4a1 significantly regulated in both brain and heart tissue after induction of ischemic CHF could be a potential link and reveals the central role of inflammation in the interrelation of the brain and the failing heart. Heart failure vs. sham-operation were performed in C57BL/6 male mice. After development of chronic heart failure (CHF) 8 weeks after the operation RNA was extracted out of prefrontal cortex, hippocampus and left ventricular myocardium in both groups. RNA of 3 ischemic CHF mice versus 6 sham operated mice was pooled and further subjected to RNA sequencing. To fabricate singular pools each probe of the group equally contributed with the final amount of 2 µg RNA per pool with the result that we had 6 different pools to be further evaluated. The mRNA profile was generated by IGA Technology, Italy (http://www.igatechnology.com/) by deep sequencing, using Illumina HiSeq 2000 platform (HiSeq). CLC-Bio Genomics Workbench software (CLC Bio, Denmark) was used to calculate gene expression levels based on Mortazavi et al. (Nat Methods. 2008;5:621-628) approach.

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MiRNA sequencing of rat hearts treated chronically with rofecoxib or its vehicle

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