Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia
Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia
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DOI：
10.1038/s41401-022-00870-1
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发表时间：
2022-02
影响因子：
8.2
通讯作者：
J. Wan;G. Wang;Fu-Ying Qin;Danling Huang;Yan Wang;Ai-Ling Su;Hai-Ping Zhang;Yang Liu;Shaoqiong Zeng;Chao-Liang Wei;Yong-Xian Cheng;Jie Liu
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作者：
J. Wan;G. Wang;Fu-Ying Qin;Danling Huang;Yan Wang;Ai-Ling Su;Hai-Ping Zhang;Yang Liu;Shaoqiong Zeng;Chao-Liang Wei;Yong-Xian Cheng;Jie Liu
儿茶酚胺能多形性室性心动过速（CPVT）是一种由儿茶酚胺引发的遗传性、致命性室性心律失常。编码心脏兰尼碱受体 (RyR2) 的基因和调节 RyR2 活性的蛋白质的突变导致舒张期 Ca2+ 通过 RyR2 通道释放（泄漏）增强，从而导致 CPVT。目前 CPVT 的治疗方法有限。我们发现从灵芝耳蜗中分离出的一种类萜Z16b以剂量依赖性方式抑制R2474S/ + 心肌细胞中的Ca2+火花频率（CaSF），IC50为3.2μM。 Z16b 还可以剂量依赖性地抑制异常的起搏后 Ca2+ 释放事件。腹腔注射 (i.p.) 肾上腺素和咖啡因会刺激所有 R2474S/+ 小鼠出现持续性室性心动过速，而 Z16b (0.5mg/kg, i.p.) 预处理可预防 10 只小鼠中的 9 只出现室性心律失常，并且在 VT 发生后立即给予 Z16b 消除了 12 只小鼠中的 9 只的 sVT。具有翻译意义，Z16b 显着抑制人 CPVT iPS-CM 中的 CaSF 和异常 Ca2+ 释放事件。从机制上讲，Z16b 与 RyR2 相互作用，增强 RyR2 N 端和中心结构域的“压缩”状态。分子对接模拟以及点突变和下拉分析发现，Z16b 与 RyR2 中的 Arg626、His1670 和 Gln2126 形成三角形氢键，锚定 NTD 和 CD 相互作用，从而将 RyR2 稳定在紧密的“拉链”构象中。我们的研究结果支持 Z16b 是一种新型 RyR2 稳定剂，可以预防 CPVT。它还可以作为具有新支架的先导化合物，用于设计更安全、更有效的治疗 CPVT 的药物。
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 fromGanoderma cochlear, inhibited Ca2+spark frequency (CaSF) in R2474S/ + cardiomyocytes in a dose-dependent manner, with an IC50of 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.