PhD Scientific Days 2024

Poster Session R - Pharmaceutical Sciences and Health Technologies 2.

Drug-induced Hidden Cardiotoxicity involves Cardiac Proteomic Changes: a Rofecoxib Case Study

Előadó neve

Dr. Weber, Bennet Y.

Neptun code

DM4UKL

Előadó munkahelye

Department of Pharmacology and Pharmacotherapy

Előadó telefonszáma

00491738621455

Előadó e-mail címe

weber.bennet@semmelweis.hu

Az előadás címe

Drug-induced Hidden Cardiotoxicity involves Cardiac Proteomic Changes: a Rofecoxib Case Study

Szerző(k) neve és munkahelye

Bennet Y. Weber¹, Gábor B Brenner¹, Barnabás Váradi¹, Bence Ágg¹, Csenger Kovácshazi¹, Kieran Wynne², David Matallanas², Péter Ferdinandy¹, Zoltán Giricz¹, Anikó Görbe¹

1: Department of Pharmacology and Pharmacotherapy
2: Systems Biology Ireland and School of Medicine, University College Dublin

Bemutatás módja

Poszter

Szekció

Poster Session R - Pharmaceutical Sciences and Health Technologies 2.

Language of the presentation

English

Preferred session

Pharmaceutical Sciences and Health Technologies

Összefoglaló szövege

Introduction and Aims:
Drug-induced cardiotoxicity is a common cause of market withdrawal. If such toxicity is not detected in clinical trials but is realised post-marketing, we define this phenomenon as hidden cardiotoxicity. Currently, the most prominent candidate of this phenomenon is the Cyclooxygenase-2 inhibitor, rofecoxib, owing to the observations from clinical and preclinical studies. We previously reported increased acute mortality in rats due to the proarrhythmic effects of the drug on the ischemic heart. However, the underlying mechanism of hidden cardiotoxicity remained unknown. Hence, we aimed to identify the molecular background of hidden cardiotoxicity induced by rofecoxib.

Methods and Results:
Rats were treated with rofecoxib or its vehicle for four weeks. RNA sequencing and proteomic datasets of left ventricular tissue samples were used for an unbiased differential expression analysis. The transcriptomic analysis showed mild alterations in the heart´s mRNA- and miRNA expression. By modelling posttranscriptional regulation in an in silico molecular correlation network, we found that the regulation exerted by miRNAs on mRNAs did not result in differential protein expression during experimental target validation by Western blot. However, proteomic data revealed that 5 phosphosites exhibited pronounced changes in their phosphorylation by q-value, and in total, 134 proteins were dysregulated in expression or on at least one of their phosphosites by p-value. Gene Ontology showed the enrichment of proteins in biological processes involving calcium ion signalling and action potential generation, implying a putative explanation for the increased fatal arrhythmias observed with rofecoxib.

Conclusion:
This is the first demonstration showing that the hidden cardiotoxic mechanisms induced by rofecoxib are based on expression changes and posttranslational modifications of several proteins in the heart. These changes are involved in calcium ion homeostasis and action potential mediated cell communication that could account for the hidden cardiotoxicity induced by rofecoxib. Whether these changes account for the hidden cardiotoxicity of other drugs needs further safety studies.

Funding:
NKFIA: NVKP-16-1-2016-0017; NKFIH: K139237, K1039105; 2020-4.1.1.-TKP2020; RRF-2.3.1-21-2022-00003; HUN-REN; 18/RI/5702; EFOP-3.6.3-VEKOP-16-2017-00009.

University

Semmelweis University

Supervisor

Anikó Görbe

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

8021

Start

16:50

End

16:53