Cyclooxygenase-2 inhibition improves hypercholesterolemia-induced cardiac dysfunction.

Area of Science:

• Cardiovascular Pharmacology
• Drug-Induced Cardiotoxicity
• Metabolic Cardiomyopathy

Background:

• Hidden cardiotoxicity manifests in diseased hearts.
• Selective cyclooxygenase-2 inhibitors like rofecoxib can exhibit proarrhythmic hidden cardiotoxicity.
• Metabolic comorbidities, such as hypercholesterolemia (HC), may worsen hidden cardiotoxicity.

Purpose of the Study:

• To investigate the hidden cardiotoxic effects of rofecoxib in the context of hypercholesterolemia.
• To determine if rofecoxib exacerbates or ameliorates cardiac dysfunction in hypercholesterolemic rats.
• To explore the molecular mechanisms underlying rofecoxib's effects on the hypercholesterolemic heart.

Main Methods:

• Rats were fed a high-cholesterol diet for 12 weeks to induce hypercholesterolemia.
• Rats received rofecoxib treatment (5.12 mg/kg) for four weeks.
• RNA sequencing was performed to analyze gene and miRNA expression changes in cardiac tissue.

Main Results:

• Rofecoxib treatment surprisingly improved mild cardiac dysfunction induced by hypercholesterolemia.
• Cardiac function markers, including end-diastolic pressure, stroke work, and mechanical efficiency, were restored by rofecoxib.
• RNA sequencing revealed significant alterations in 28 miRNAs and 300 genes due to HC, with rofecoxib reversing changes in specific miRNAs (miR-27a-5p, miR-30d-5p) and genes (Cdc42ep4, Cox5, Cxcl9).

Conclusions:

• This study provides the first evidence that rofecoxib can improve hypercholesterolemia-induced cardiac dysfunction.
• The beneficial effects of rofecoxib involve modulation of gene expression profiles, including key regulators of its action.
• Rofecoxib's impact on hidden cardiotoxicity in metabolic conditions warrants further investigation.