Cyclooxygenase-2 inhibition improves hypercholesterolemia-induced cardiac dysfunction

Hidden cardiotoxicity is defined as cardiotoxicity of a drug that manifests only in the diseased heart. We have previously shown that the proarrhythmic hidden cardiotoxic properties of a model drug, the selective cyclooxygenase-2 inhibitor rofecoxib, can be revealed in preclinical models of ischemia/reperfusion injury. As metabolic comorbidities, such as hypercholesterolemia (HC), may exacerbate hidden cardiotoxicity, we aimed to investigate the hidden cardiotoxic effects of the model drug, rofecoxib, in the presence of hypercholesterolemia. Rats were fed a high-cholesterol diet for 12 weeks and treated with 5.12 mg/kg rofecoxib. Four weeks of rofecoxib treatment surprisingly improved HC-induced mild cardiac dysfunction by restoring end-diastolic pressure, stroke work, and mechanical efficiency. Then, RNA sequencing revealed that the expression of 28 miRNAs and 300 genes was significantly altered in the HC-fed group. The HC-induced expression changes of miR-27a-5p and miR-30d-5p were reversed by rofecoxib treatment. Cdc42ep4, Cox5, and Cxcl9 genes were also counter-regulated following rofecoxib treatment compared to HC-induced changes. This is the first demonstration that rofecoxib improves HC-induced cardiac dysfunction, with the mechanism involving changes in the gene expression profile, including some key regulators of rofecoxib action.