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

doi:10.1038/s41401-022-00870-1

	Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia
	Wan, Jiang-fan 1,2; Wang, Gang 1; Qin, Fu-ying 3; Huang, Dan-ling 3; Wang, Yan 4; Su, Ai-ling 4; Zhang, Hai-ping 5; Liu, Yang 6; Zeng, Shao-yin 7; Wei, Chao-liang 1; Cheng, Yong-xian 3; Liu, Jie 1
	2022-02-21
发表期刊	ACTA PHARMACOLOGICA SINICA
ISSN	1671-4083
页码	11
摘要	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 mu M. 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.
关键词	arrhythmia catecholaminergic polymorphic ventricular tachycardia natural product ryanodine receptor induced pluripotent stem cell-derived cardiomyocytes
DOI	10.1038/s41401-022-00870-1
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[81970250] ; National Natural Science Foundation of China[31671179] ; Natural Science Foundation of Guangdong, China[2021A1515010787] ; Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis[ZDSYS20190902092903 237] ; Basic Research Foundation of Shenzhen[JCYJ20180508152222104] ; Basic Research Foundation of Shenzhen[JCYJ20190808123018993] ; Basic Research Foundation of Shenzhen[JCYJ20190808121819024] ; Basic Research Foundation of Shenzhen[JCYJ2 0210324094006018] ; Shenzhen Science and Technology Innovation Committee Project[JCYJ20180507182239272]
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
WOS类目	Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS记录号	WOS:000759008100001
出版者	NATURE PUBL GROUP
引用统计	被引频次：5[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.204/handle/2XEOYT63/18959
专题	中国科学院计算技术研究所期刊论文_英文
通讯作者	Cheng, Yong-xian; Liu, Jie
作者单位	1.Shenzhen Univ, Sch Med, Dept Pathophysiol, Guangdong Key Lab Genome Stabil & Human Dis Preve, Shenzhen 518000, Peoples R China 2.Shenzhen Univ, Coll Phys & Optoelect Engn, Shenzhen 518060, Peoples R China 3.Shenzhen Univ, Sch Pharmaceut Sci, Hlth Sci Ctr, Shenzhen 518000, Peoples R China 4.Chinese Acad Sci, Ctr Translat Med Res & Dev, Shenzhen Inst Adv Technol, Shenzhen 518000, Peoples R China 5.Chinese Acad Sci, Ctr High Performance Comp, Joint Engn Res Ctr Hlth Big Data Intelligent Anal, Shenzhen Inst Adv Technol, Shenzhen 518000, Peoples R China 6.Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Guangzhou 510000, Peoples R China 7.Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Dept Pediat Cardiol, Guangzhou 510000, Peoples R China
推荐引用方式 GB/T 7714	Wan, Jiang-fan,Wang, Gang,Qin, Fu-ying,et al. Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia[J]. ACTA PHARMACOLOGICA SINICA,2022:11.
APA	Wan, Jiang-fan.,Wang, Gang.,Qin, Fu-ying.,Huang, Dan-ling.,Wang, Yan.,...&Liu, Jie.(2022).Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia.ACTA PHARMACOLOGICA SINICA,11.
MLA	Wan, Jiang-fan,et al."Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia".ACTA PHARMACOLOGICA SINICA (2022):11.