Article

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

Jiang-fan Wan1,2, Gang Wang1, Fu-ying Qin3, Dan-ling Huang3, Yan Wang4, Ai-ling Su4, Hai-ping Zhang5, Yang Liu6, Shao-yin Zeng7, Chao-liang Wei1, Yong-xian Cheng3, Jie Liu1
1 Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518000, China
2 College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
3 School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518000, China
4 Center for Translation Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China
5 Center for High Performance Computing, Joint Engineering Research Center for Health Big Data Intelligent Analysis Technology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China
6 Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
7 Guangdong Provincial key laboratory of South China Structure Heart Disease, Department of Pediatric Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
Correspondence to: Yong-xian Cheng: yxcheng@szu.edu.cn, Jie Liu: liuj@szu.edu.cn,
DOI: 10.1038/s41401-022-00870-1
Received: 24 August 2021
Accepted: 17 January 2022
Advance online: 21 February 2022

Abstract

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.
Keywords: arrhythmia; catecholaminergic polymorphic ventricular tachycardia; natural product; ryanodine receptor; induced pluripotent stem cell-derived cardiomyocytes

Article Options

Download Citation

Cited times in Scopus

Share