Innovation of treatment for malignant hyperthermia and arrhythmia by inhibition of abnormal intracellular Ca2+ release through the ryanodine receptor

通过兰尼碱受体抑制细胞内异常Ca2+释放治疗恶性高热和心律失常的创新

• 批准号: 20591805
• 负责人: KOBAYASHI Shigeki
• 金额: $ 3万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591805/
• 关键词: 悪性高熱症; 心室頻拍症; 心不全; ダントロレン; リアノジン受容体; 不整脈

Dantrolene, a specific drug for the treatment of malignant hyperthermia, was found to inhibit Ca^<2+> leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal(1-619 amino acid) amd central (2000-2500 amino acid) domains of RyRs. Here, we examined 1)the effect of dantrolene on the Ca2+ release and cardiomyocyte function in chronic rapid pacing-induced heart failure dog model 2) the anti-arrhythmic effect of dantrolene in human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model. In heart failure model, dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca^<2+> leak, in turn improves cardiomyocyte function in failing hearts. In human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model, dantrolene prevents CPVT, presumably by correction of catecholamine-induced defective inter-domain interaction within RyR2inhibiting and inhibition of Ca^<2+> leak through RyR2. Thus, dantrolene may have a potential to treat heart failure and lethal arrhythmia, specifically targeting RyR2.

丹曲林是一种治疗恶性高热的特效药物，被发现不仅可以通过骨骼兰尼碱受体（RyR1）抑制Ca^2+渗漏，还可以通过纠正有缺陷的结构域间缺陷来抑制心脏兰尼碱受体（RyR2）的Ca^2+渗漏。 RyRs N 端（1-619 个氨基酸）和中央（2000-2500 个氨基酸）结构域之间的相互作用。在这里，我们检查了 1) 丹曲林对慢性快速起搏诱发的心力衰竭狗模型中 Ca2+ 释放和心肌细胞功能的影响 2) 丹曲林在人 CPVT 相关 RyR2^<R2474S />knock- 中的抗心律失常作用在（KI）小鼠模型中。在心力衰竭模型中，丹曲林纠正衰竭心脏中RyR2内有缺陷的域间相互作用，抑制自发Ca ^ 2+ 渗漏，进而改善衰竭心脏中的心肌细胞功能。在人 CPVT 相关的 RyR2^<R2474S /+> 敲入 (KI) 小鼠模型中，丹曲林可预防 CPVT，可能是通过纠正儿茶酚胺诱导的 RyR2 抑制内的有缺陷的域间相互作用和抑制 Ca^2+ 渗漏来预防 CPVT。 RyR2。因此，丹曲林可能具有治疗心力衰竭和致命性心律失常的潜力，特别是针对 RyR2。

项目成果

Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model

• DOI: 10.1253/circj.cj-10-0680
• 发表时间: 2010-12-01
• 期刊: CIRCULATION JOURNAL
• 影响因子: 3.3
• 作者: Kobayashi, Shigeki;Yano, Masafumi;Matsuzaki, Masunori
• 通讯作者: Matsuzaki, Masunori

Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure

• DOI: 10.1093/cvr/cvq108
• 发表时间: 2010-09-01
• 期刊: CARDIOVASCULAR RESEARCH
• 影响因子: 10.8
• 作者: Ono, Makoto;Yano, Masafumi;Matsuzaki, Masunori
• 通讯作者: Matsuzaki, Masunori

Mutation-linked Defective Domain Interaction within the Ryanodine Receptor Causes Ca2+ Leak Leading to Catecholaminergic Polymorphic Ventricular Tachycardia

Ryanodine 受体内突变相关的缺陷结构域相互作用导致 Ca2 泄漏，导致儿茶酚胺能多形性室性心动过速

• 发表时间: 2010
• 作者: Suetomi T;Yano M;Fukuda M;Hino A;Ono M;Xu X;Susa T;Uchinoumi H;Oda T;Okuda S;Kobayashi S;Yamamoto T;Ikeda Y;Matsuzaki M.
• 通讯作者: Matsuzaki M.

Masunori Matsuzaki Urinary 8-Hydroxy-2'-Deoxyguanosine is a Biomarker for Evaluating the Inflammatory Activity and the Effectiveness to Corticosteroids in Patients with Cardiac Sarcoidosis.

Masunori Matsuzaki 尿 8-羟基-2-脱氧鸟苷是评估心脏结节病患者炎症活动和皮质类固醇有效性的生物标志物。

• 发表时间: 2010
• 作者: Takeo Tanaka;Shigeki Kobayashi;Takehisa Susa;Shinichi Okuda;Masahiro Doi;Yasuaki Wada;Jutaro Yamada;Takeshi Ueyama;Takayuki Okamura;Shuji Kawamura;Masafumi Yano
• 通讯作者: Masafumi Yano

Mechanism of Destabilized RyR2 Channel in Catecholaminergic Polymorphic Ventricular Tachycardia

儿茶酚胺能多形性室性心动过速中 RyR2 通道失稳的机制

• 发表时间: 2010
• 作者: 濱田隆太;柿沼孝泰;武田明子;平林清子;本間豊彦;内野博之;Takeshi Suetomi
• 通讯作者: Takeshi Suetomi