PXD050504-1

PXD050504 is an original dataset announced via ProteomeXchange.

Title	Assessment of the molecular mechanisms of drug-induced hidden cardiotoxicity by a multi-omics approach: the example of rofecoxib
Description	1.1 Background and Purpose Hidden 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. 1.2 Experimental Approach and Key Results Rats 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. 1.3 Conclusion and Implications This 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.
HostingRepository	PRIDE
AnnounceDate	2025-06-20
AnnouncementXML	Submission_2025-06-20_11:47:36.721.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Wynne
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-10 05:53:52	ID requested
⏵ 1	2025-06-20 11:47:37	announced

10.1111/BPH.70106;

submitter keyword: Cardiac protein expression,Rofecoxib, Phosphorylation.

Anikó Görbe
contact affiliation	HUN-REN–SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Pharmahungary Group, Záhony utca 7, 1031 Budapest, Hungary
contact email	gorbe.aniko@semmelweis.hu
lab head
Kieran Wynne
contact affiliation	University College Dublin
contact email	kieran.wynne1@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050504
     1. Label: PRIDE project
     2. Name: Assessment of the molecular mechanisms of drug-induced hidden cardiotoxicity by a multi-omics approach: the example of rofecoxib