Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Area of Science:

• Cardiovascular Science
• Pharmacology
• Molecular Biology

Background:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase-2 (COX-2) are associated with increased risks of heart failure and hypertension.
• The precise mechanisms underlying these cardiovascular adverse effects remain incompletely understood.

Purpose of the Study:

• To investigate the direct role of cyclooxygenase-2 (COX-2) in cardiomyocytes on cardiac function and response to stress.
• To elucidate the impact of cardiomyocyte-specific COX-2 inhibition on cardiac performance and pathological remodeling.

Main Methods:

• Utilized a mouse model with a floxed COX-2 gene crossed into merCremer mice under the alpha-myosin heavy-chain promoter.
• Administered tamoxifen to induce selective deletion of COX-2 specifically in cardiomyocytes.
• Assessed cardiac output, exercise tolerance, arrhythmogenesis, and cardiac remodeling (hypertrophy, fibrosis) following pressure overload.

Main Results:

• Selective deletion of COX-2 in cardiomyocytes led to depressed cardiac output, weight loss, and reduced exercise tolerance.
• Mice with cardiomyocyte-specific COX-2 deficiency exhibited enhanced susceptibility to induced arrhythmogenesis.
• Cardiac dysfunction induced by pressure overload showed progressive recovery in knockouts, accompanied by increased cardiomyocyte hypertrophy and fibrosis.

Conclusions:

• Inhibition of COX-2 within cardiomyocytes contributes to cardiac dysfunction and adverse remodeling.
• These findings suggest that COX-2 inhibition in cardiomyocytes may play a role in the development of heart failure in patients using selective COX-2 inhibitors.