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

文献类型：期刊论文

作者Wan, Jiang-fan2,3; Wang, Gang2; Qin, Fu-ying4; Huang, Dan-ling4; Wang, Yan5; Su, Ai-ling5; Zhang, Hai-ping6; Liu, Yang7; Zeng, Shao-yin1; Wei, Chao-liang2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2022-02-21
页码11
关键词arrhythmia catecholaminergic polymorphic ventricular tachycardia natural product ryanodine receptor induced pluripotent stem cell-derived cardiomyocytes
ISSN号1671-4083
DOI10.1038/s41401-022-00870-1
英文摘要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.
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
语种英语
WOS记录号WOS:000759008100001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.204/handle/2XEOYT63/18958]  
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.Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Dept Pediat Cardiol, Guangzhou 510000, Peoples R China
2.Shenzhen Univ, Sch Med, Dept Pathophysiol, Guangdong Key Lab Genome Stabil & Human Dis Preve, Shenzhen 518000, Peoples R China
3.Shenzhen Univ, Coll Phys & Optoelect Engn, Shenzhen 518060, Peoples R China
4.Shenzhen Univ, Sch Pharmaceut Sci, Hlth Sci Ctr, Shenzhen 518000, Peoples R China
5.Chinese Acad Sci, Ctr Translat Med Res & Dev, Shenzhen Inst Adv Technol, Shenzhen 518000, Peoples R China
6.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
7.Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, 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.

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来源：计算技术研究所

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