Caveolin-3 and Caveolae regulate ventricular repolarization

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cardiac Electrophysiology

Background:

• Caveolae, flask-shaped invaginations of the cardiomyocyte sarcolemma, depend on caveolin-3 (Cav-3) and are crucial for hosting ion channels and signaling molecules.
• Reduced Cav-3 expression is linked to heart failure models, and CAV3 variants are associated with long-QT syndrome, but the direct impact of Cav-3 levels on arrhythmias is unclear.

Purpose of the Study:

• To investigate the electrophysiological consequences of cardiac-specific Cav-3 ablation in adult mice.

Main Methods:

• Generated cardiac-specific, inducible Cav-3 homozygous knockout (Cav-3KO) mice.
• Assessed cardiac structure, function, and electrophysiology using Western blot, electron microscopy, ECG, and isolated myocyte electrophysiology.
• Utilized mathematical modeling and human iPSC-derived cardiomyocytes to validate findings.

Main Results:

• Cav-3 ablation led to loss of caveolae but preserved cardiac structure and function.
• Cav-3KO mice exhibited prolonged QTc intervals and increased susceptibility to ventricular arrhythmias.
• Myocytes from Cav-3KO mice showed prolonged action potential duration due to altered potassium and calcium/sodium currents.

Conclusions:

• Caveolin-3 and caveolae are essential regulators of cardiac repolarization.
• Cav-3 modulates multiple ionic currents, influencing arrhythmia risk.
• Disrupting Cav-3 function is sufficient to cause significant electrophysiological abnormalities and pro-arrhythmic changes.