PhD Scientific Days 2025

Poster Session III. - H: Pharmaceutical Sciences and Health Technologies

Rosiglitazone does not cause cardiotoxic gene expression changes in healthy rat hearts

Name of the presenter

Weber Bennet Y.

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy

Authors

Bennet Weber¹, Gábor B Brenner¹, Barnabás Váradi¹, Bence Ágg¹, Kieran Wynne², David Matallanas², Péter Ferdinandy¹, Zoltán Giricz¹, Anikó Görbe¹, Zoltán AndrásBereczki¹, Sevda Aliyeva¹, Eman Payam Esfahani¹

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

Text of the abstract

Introduction and Aims:
Rosiglitazone, a thiazolidinedione-type antidiabetic, was withdrawn by the EMA and placed under temporary marketing restrictions by the FDA due to cardiotoxicity concerns. The discrepancy in marketing authorisation in the EU and USA and the inconsistency of clinical observations led us to investigate the molecular mechanism of rosiglitazone-induced potential cardiotoxicity. Therefore, here we investigated the cardiac gene expression levels by an unbiased multi-omics approach after chronic rosiglitazone treatment in rats.

Method:
Rats were treated with 0.8 mg/kg rosiglitazone or its vehicle for 28 days. Messenger RNA (mRNA) sequencing and mass-spectrometry-based proteomics of left ventricular tissue samples were used for a differential gene expression analysis.

Results:
Rosiglitazone caused mild gene expression alterations in the heart at the transcript and protein levels. The four mRNAs that exhibited differential expression were selected for experimental target validation by Western blot. Neither of the selected genes exhibited differential protein expression, demonstrating a low correlation between mRNAs and proteins. The mass-spectrometry-based proteomics revealed five proteins that were differentially expressed. Interestingly, the differentially expressed proteins were downregulated without changes in their mRNA levels, which further demonstrates a low correlation between mRNA and protein expression.

Conclusion:
This is the first demonstration that chronic rosiglitazone treatment causes mild cardiac gene expression changes in healthy hearts. These changes cannot be associated with cardiotoxicity. Although some cardiac side effects have been reported in the clinical arena, here, we were unable to reveal a rosiglitazone-induced cardiotoxic mechanism using transcriptomic and proteomic technologies in a preclinical study. However, cardiotoxic gene expression changes may manifest only in the presence of comorbidities.

Funding:
- National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program)
- National Research, Development and Innovation Office of Hungary (NKFIH; K139237 to Anikó Görbe)
- Bennet Y Weber: EFOP-3.6.3-VEKOP-16-2017-00009 and 2024-2.1.1-EKÖP-2024-00004 University Research Scholarship Programme of the Ministry for Culture and Innovation