Hypercholesterolemia interferes with the cardioprotective and hidden cardiotoxic effects of rofecoxib
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ABSTRACT:
PROVIDER: PRJEB74299 | ENA |
REPOSITORIES: ENA
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Project description:Rofecoxib, a cyclooxygenase-2 enzyme inhibitor, was withdrawn from the market after revealing its proarrhythmic and prothrombotic effects in phase IV clinical trials. Currently, in the preclinical phase of drug development, the cardiac side effects are tested on healthy tissues or small animals. Metabolic comorbidities, like hypercholesterolemia, may interfere with the cardioprotective or carditoxic effects of specific drugs. Here, we aimed to develop a test platform to investigate the cardiac effects of drugs in models with metabolic comorbidities. We fed adult, male Wistar rats for 12 weeks of high-fat diet (2% cholesterol + 0.25% cholic acid-enriched chow) or standard chow and treated high-fat diet-fed rats with 5.12 mg/kg rofecoxib for the last 4 weeks of the diet. Then, we performed RNA-seq from the left ventricles of the animals, to investigate the gene expression changes following high-fat diet and rofecoxib treatments.
2024-07-01 | E-MTAB-13958 | biostudies-arrayexpress
Project description:Rofecoxib, a cyclooxygenase-2 enzyme inhibitor, was withdrawn from the market after revealing its proarrhythmic and prothrombotic effects in phase IV clinical trials. Currently, in the preclinical phase of drug development, the cardiac side effects are tested on healthy tissues or small animals. Metabolic comorbidities, like hypercholesterolemia, may interfere with the cardioprotective or carditoxic effects of specific drugs. Here, we aimed to develop a test platform to investigate the cardiac effects of drugs in models with metabolic comorbidities. We fed adult, male Wistar rats for 12 weeks of high-fat diet (2% cholesterol + 0.25% cholic acid-enriched chow) or standard chow and treated high-fat diet-fed rats with 5.12 mg/kg rofecoxib for the last 4 weeks of the diet. Then, we performed microRNA sequencing from the left ventricles of the animals, to investigate the gene expression changes following high-fat diet and rofecoxib treatments.
2024-07-01 | E-MTAB-13960 | biostudies-arrayexpress
Project description: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.
2024-10-30 | E-MTAB-13913 | biostudies-arrayexpress
Project description: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.
2024-10-30 | E-MTAB-13909 | biostudies-arrayexpress
Project description:MicroRNA profiling of rat left ventricles to investigate the hidden cardiac effects of rofecoxib in hypercholesterolemia
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Project description:Celecoxib, Rofecoxib Gavage Treated Mice, Aorta RNA-Seq
2020-03-07 | GSE97066 | GEO
Project description:Celecoxib, Rofecoxib Chronically Treated Mice, Aorta RNA-Seq
2020-03-07 | GSE95802 | GEO
Project description:We screen for vascular off-target effects at therapeutic concentrations of celecoxib and rofecoxib using genomic approaches in a mouse model of vascular inflammatory responses. We assess whether therapeutic concentrations of celecoxib and rofecoxib might elicit distinct genomic effects in vivo in mice by comprehensive and unbiased analysis of the whole transcriptome sequencing. Drug specific differences in their expression profiles would be indicative of off-target effects.
2020-02-28 | GSE95500 | GEO
Project description:The aim of this data set is to measure the effect of rofecoxib and celecoxib on the transcription profile in an in vitro inflammation model. Transcription profiling was carried out using Affymetrix HG U-133A v2 microarrays.
2015-04-20 | GSE59671 | GEO
Project description:The aim of this data set is to measure the effect of rofecoxib and celecoxib on the transcription profile in an in vitro inflammation model. Transcription profiling was carried out using Affymetrix HG U-133A v2 microarrays. Human aortic smooth muscle cells (3F1243) were pre-treated with rofecoxib (500 nM) or celecoxib (500 nM) for two hours and subsequently exposed to IL-1beta (10 ng/ml). Transcription profiling was carried out at several time points of IL-1beta exposure: Four samples at -2 hours. Four samples each of control, celecoxib, and rofecoxib at each time point 0hr, 2hr, 8hr and 24hr. 52 samples in total.
2015-04-20 | E-GEOD-59671 | biostudies-arrayexpress