Intracellular Mechanism of Rosuvastatin-Induced Decrease in Mature hERG Protein Expression on Membrane.

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Drug Safety

Background:

• The hERG potassium channel (IKr) is critical for cardiac repolarization.
• Decreased IKr function can lead to long QT syndrome and potentially fatal arrhythmias.
• Statins, including rosuvastatin, have been implicated in IKr inhibition.

Purpose of the Study:

• To elucidate the mechanism of rosuvastatin-induced hERG current reduction.
• To assess the potential for rosuvastatin-induced cardiac toxicity.
• To investigate rosuvastatin's effects on hERG channel expression, trafficking, and degradation.

Main Methods:

• Utilized induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
• Assessed hERG currents, action potential duration (APD), and QTc intervals.
• Investigated protein expression, transcription factor activity (Sp1, ATF6), chaperone involvement (Hsp70, calnexin, calreticulin), and degradation pathways (lysosomes, proteasomes).

Main Results:

• Rosuvastatin reduced hERG currents by accelerating inactivation and prolonging APD.
• It decreased mature hERG expression, involving Sp1 transcription factor.
• Rosuvastatin impaired hERG trafficking by reducing Hsp70 interaction and activated the UPR pathway via ATF6.
• Both lysosomal and proteasomal degradation pathways were upregulated, increasing hERG channel turnover.
• Significant blockade of hERG current, prolonged APDs, and QTc intervals were observed.

Conclusions:

• Rosuvastatin reduces hERG plasma membrane expression through impaired trafficking and increased degradation.
• It potently blocks hERG current, delays cardiac repolarization, and prolongs APDs and QTc intervals.
• Caution is advised when prescribing rosuvastatin, particularly with other QT-prolonging medications.