PhD Scientific Days 2025

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

Cox-2 Inhibition Surprisingly Improves Cardiac Function in Hypercholesterolemic Rats

Name of the presenter

Nagy Regina Norma

Institute/workplace of the presenter

Semmelweis University, Department of Pharmacology and Pharmacotherapy

Authors

Regina N. Nagy¹, Bernadett Kiss¹, Gábor Brenner¹, Barnabás Váradi¹, Bence Ágg¹, András Makkos¹, Csenger Kovácsházi¹, Nabil V. Sayour¹, Tamás G. Gergely¹, Mihály Ruppert¹, Tamás Radovits¹, Béla Merkely¹, Zoltán V. Varga¹, Zoltán Giricz¹, Péter Ferdinandy¹, Anikó Görbe¹

1: Semmelweis University

Text of the abstract

Introduction: Hidden cardiotoxicity is when a drug's adverse cardiac effects appear only in diseased hearts. We previously showed the hidden cardiotoxicity of a cyclooxygenase-2 inhibitor, our model drug, rofecoxib in preclinical ischemia/reperfusion injury models. Metabolic comorbidities like hypercholesterolemia (HC) may worsen this phenomenon.
Aims: We aimed to examine rofecoxib's hidden cardiotoxic impact in hypercholesterolemic rats, analyzing cardiac gene expression changes.
Method: Rats received a high-cholesterol diet for 12 weeks and 5.12 mg/kg rofecoxib per os, or vehicle treatment for the last 4 weeks of the diet. As a control, we used standard diet-fed animals treated with vehicle only. We measured cardiac functional parameters by pressure-volume analysis. We performed small RNA and RNA sequencing from the left ventricular samples of the animals to determine the differentially expressed genes.
Results: Surprisingly, rofecoxib treatment improved the HC-induced mild cardiac dysfunction, by restoring end-diastolic pressure, stroke work, and mechanical efficiency. We found that HC significantly altered the expression of 28 miRNAs and 300 mRNAs. Rofecoxib treatment reversed the HC-induced expression changes of miR-27a-5p and miR-30d-5p. Furthermore, rofecoxib treatment, compared to HC, also reversed Cdc42ep4, Cox5, and Cxcl9 gene expression, which likely contributed to improved cardiac function.
Conclusion: This study is the first to demonstrate that rofecoxib unexpectedly enhances cardiac dysfunction impaired by HC. We identified the underlying molecular mechanism as alterations in gene expression patterns. Our findings enhance the understanding of how the metabolic state influences the hidden cardiotoxic properties of pharmaceutical agents.
Funding: This study was supported by the EKÖP-2024-29 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund. This study was supported by the SE250+ Excellence PhD Scholarship by Semmelweis University. The study was supported by the National Research, Development and Innovation Office of Hungary (K139237, RRF-2.3.1-21-2022-00003).