Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, lethal ventricular
arrhythmia triggered by
catecholamines. Mutations in genes that encode cardiac
ryanodine receptor (
RyR2) and
proteins that regulate
RyR2 activity cause enhanced diastolic Ca2+ release (leak) through the
RyR2 channels, resulting in CPVT. Current
therapies for CPVT are limited. We found that Z16b, a meroterpenoid isolated from Ganoderma cochlear, inhibited Ca2+ spark frequency (CaSF) in R2474S/ + cardiomyocytes in a dose-dependent manner, with an IC50 of 3.2 μM. Z16b also dose-dependently suppressed abnormal post-pacing Ca2+ release events.
Intraperitoneal injection (i.p.) of
epinephrine and
caffeine stimulated sustained
ventricular tachycardia in all R2474S/+ mice, while pretreatment with Z16b (0.5 mg/kg, i.p.) prevented ventricular
arrhythmia in 9 of 10 mice, and Z16b administration immediately after the onset of VT abolished sVT in 9 of 12 mice. Of translational significance, Z16b significantly inhibited CaSF and abnormal Ca2+ release events in human CPVT iPS-CMs. Mechanistically, Z16b interacts with
RyR2, enhancing the "zipping" state of the N-terminal and central domains of
RyR2. A molecular docking simulation and point mutation and pulldown assays identified Z16b forms hydrogen bonds with Arg626, His1670, and Gln2126 in
RyR2 as a triangle shape that anchors the NTD and CD interaction and thus stabilizes
RyR2 in a tight "zipping" conformation. Our findings support that Z16b is a novel
RyR2 stabilizer that can prevent CPVT. It may also serve as a lead compound with a new scaffold for the design of safer and more efficient drugs for treating CPVT.