Progesterone modulates SERCA2a expression and function in rabbit cardiomyocytes.

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Pharmacology

Background:

• Long QT syndrome type 2 (LQT2) is associated with arrhythmias and sudden cardiac death.
• Progesterone treatment demonstrated efficacy in abolishing arrhythmias in a transgenic LQT2 rabbit model.
• Elevated cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase type 2a (SERCA2a) levels were observed in LQT2 hearts.

Purpose of the Study:

• To investigate the hypothesis that progesterone upregulates SERCA2a expression, thereby reducing calcium-dependent arrhythmias in LQT2 rabbits.
• To elucidate the effect of progesterone on SERCA2a regulation at the protein and cellular levels.

Main Methods:

• Primary cardiomyocyte cultures from neonatal rabbits were treated with progesterone and pharmacological agents.
• Protein abundance of SERCA2a was assessed using immunoblotting in total cell lysates and sarcoplasmic reticulum-enriched fractions.
• mRNA levels were quantified via real-time PCR, and cellular calcium handling was evaluated using digital imaging.

Main Results:

• Progesterone treatment increased total SERCA2a protein levels by inhibiting its degradation pathway.
• Progesterone significantly reduced the ubiquitination of SERCA2a polypeptides, indicating stabilization of the protein.
• Digital imaging confirmed that progesterone shortened the decay and duration of intracellular calcium transients.

Conclusions:

• Progesterone enhances SERCA2a protein levels and activity in cardiomyocytes.
• Progesterone stabilizes SERCA2a, at least partially, by decreasing its ubiquitination.
• These findings provide a molecular mechanism for progesterone's antiarrhythmic effects in LQT2.