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Assessment of the molecular mechanisms of drug-induced hidden cardiotoxicity by a multi-omics approach: the example of rofecoxib

ABSTRACT: 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.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

DISEASE(S): Myocardial Ischemia

SUBMITTER: Kieran Wynne

LAB HEAD: Anikó Görbe

PROVIDER: PXD050504 | Pride | 2025-06-20

REPOSITORIES: Pride

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			Action	DRS
	221229kw_PHunRcoxHeart_PH_LV101_S2-A10_1_12867.d.zip	Other
	221229kw_PHunRcoxHeart_PH_LV101_S2-A9_1_12866.d.zip	Other
	221229kw_PHunRcoxHeart_PH_LV102_S2-A5_1_12862.d.zip	Other
	221229kw_PHunRcoxHeart_PH_LV102_S2-A6_1_12863.d.zip	Other
	221229kw_PHunRcoxHeart_PH_LV103_S1-B7_1_12903.d.zip	Other

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Assessment of the molecular mechanisms of drug-induced hidden cardiotoxicity by a multi-omics approach: the example of rofecoxib

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