Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing

Area of Science:

• Cardiovascular Physiology
• Cellular Electrophysiology
• Membrane Biology

Background:

• Mechanical stretch of cardiac muscle influences action potential propagation, potentially leading to arrhythmias.
• The precise mechanisms by which stretch affects cardiac conduction are not fully understood.
• Previous research suggests a role for caveolae conformation changes in myocytes.

Purpose of the Study:

• To test the hypothesis that stretch-induced slowing of cardiac action potential conduction is dependent on caveolae.
• To elucidate the role of caveolae in mediating the effects of mechanical stretch on cardiac electrophysiology.

Main Methods:

• Optical mapping of action potential propagation velocity in isolated mouse hearts and cardiomyocyte cultures.
• Assessment of stretch-activated channel blockade using gadolinium and GsMTx-4.
• Investigation of caveolae disruption via genetic deletion of caveolin-3 (Cav3 KO) and cholesterol depletion.
• Electron microscopy to observe caveolae recruitment.
• Measurement of cell membrane capacitance, electrical time constant, and lipid recruitment.

Main Results:

• Cardiac action potential propagation velocity decreased with stretch in wild-type but not Cav3 KO mice.
• Stretch-dependent conduction slowing was inhibited by caveolae disruption (Cav3 KO, cholesterol depletion).
• Stretch induced recruitment of caveolae to the sarcolemma and increased cell membrane capacitance and electrical time constant in wild-type myocytes.

Conclusions:

• Caveolae are essential for the conduction slowing observed during cardiac myocyte stretch.
• Recruitment of caveolae to the sarcolemma during stretch increases cell membrane capacitance, thereby slowing ventricular action potential propagation.
• This mechanism highlights the functional importance of caveolae in cardiac electrophysiology and mechanotransduction.