Hypercholesterolemia interferes with the cardioprotective and hidden cardiotoxic effects of rofecoxib

Rofecoxib, a cyclooxygenase-2 enzyme inhibitor, was withdrawn from the market after revealing its proarrhythmic and prothrombotic effects in phase IV clinical trials. Currently, in the preclinical phase of drug development, the cardiac side effects are tested on healthy tissues or small animals. Metabolic comorbidities, like hypercholesterolemia, may interfere with the cardioprotective or carditoxic effects of specific drugs. Here, we aimed to develop a test platform to investigate the cardiac effects of drugs in models with metabolic comorbidities. We fed adult, male Wistar rats for 12 weeks of high-fat diet (2% cholesterol + 0.25% cholic acid-enriched chow) or standard chow and treated high-fat diet-fed rats with 5.12 mg/kg rofecoxib for the last 4 weeks of the diet. Then, we performed RNA-seq from the left ventricles of the animals, to investigate the gene expression changes following high-fat diet and rofecoxib treatments.