Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic...

Area of Science:

• Cardiovascular Research
• Molecular Pharmacology
• Genetics and Inherited Diseases

Background:

• Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmia caused by abnormal calcium (Ca2+) release from the cardiac ryanodine receptor (RyR2).
• Current CPVT therapies are limited, highlighting the need for novel treatment strategies targeting RyR2 dysfunction.

Purpose of the Study:

• To investigate the potential of Z16b, a meroterpenoid from Ganoderma cochlear, as a therapeutic agent for CPVT.
• To elucidate the mechanism by which Z16b modulates RyR2 activity and prevents ventricular arrhythmias.

Main Methods:

• Assessed Z16b's effect on Ca2+ spark frequency (CaSF) and abnormal Ca2+ release in cardiomyocytes from CPVT mouse models and human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs).
• Evaluated Z16b's efficacy in preventing and treating ventricular tachycardia in CPVT mice challenged with catecholamines.
• Utilized molecular docking, point mutation, and pulldown assays to determine Z16b's interaction with RyR2.

Main Results:

• Z16b significantly inhibited CaSF and abnormal Ca2+ release in a dose-dependent manner in both mouse and human CPVT models.
• Pretreatment with Z16b prevented epinephrine- and caffeine-induced ventricular tachycardia in 90% of CPVT mice, and administration post-VT onset abolished arrhythmia in 75% of mice.
• Z16b stabilizes RyR2 by enhancing its 'zipping' conformation through hydrogen bonds with key residues, as confirmed by molecular and biochemical analyses.

Conclusions:

• Z16b acts as a novel RyR2 stabilizer, effectively preventing and treating catecholaminergic polymorphic ventricular tachycardia.
• Z16b demonstrates significant translational potential and may serve as a lead compound for developing safer and more effective CPVT therapeutics.