The therapeutic approach of inductive lethal arrhythmia by inhibiting Ca2+ leak through the cardiac ryanodine receptor in hypertrophic cardiomyopathy

通过心脏兰尼碱受体抑制Ca2漏治疗肥厚型心肌病诱发致死性心律失常

• 批准号: 23790856
• 负责人: OKUDA Shinichi
• 金额: $ 2.66万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790856/
• 关键词: 肥大型心筋症; カルシウムハンドリング; リアノジン受容体; ドメイン連関; 致死性不整脈

Hypertrophic cardiomyopathy(HCM) is known to be a myocardial disorder characterized by severe hypertrophy of the left ventricule. In HCM patients, it is the cause of sudden death by lethal arrhythmia in younger age. Medical approach against inductive ventricular arrhythmia in HCM patients remains elusive. Here, we hypothesized that diastolic Ca2+ leak through Ryanodine receptor (RyR2) is one of the important factor of regulating arrhytmogenesis in HCM. To verify this hypothesis, we investigated the pathogenic role of Ca2+ leak through RyR2 in transgenic mouse (TG) model of Familial Hypertrophic cardiomyopathy-related cardiac troponin T mutation. Diastolic Ca2+ leak through defective RyR2 is induced by beta-adrenergic stimulation in TG cardiomyocytes. Dantrolene and Calmodulin-kinaseII inhibitor can inhibit Ca2+ leak by stabilizing RyR2. These results might suggest that the stabilization of RyR2 and inhibiting Ca2+ leak might play a role for the pathogenesis of lethal arrhythmia in HCM.

肥厚性心肌病（HCM）是一种以左心室严重肥大为特征的心肌疾病。在HCM患者中，它是导致年轻时致命性心律失常猝死的原因。治疗HCM患者诱发性室性心律失常的医学途径仍然难以捉摸。在这里，我们假设舒张Ca2+通过Ryanodine受体（RyR2）泄漏是调节HCM心律失常的重要因素之一。为了验证这一假设，我们研究了Ca2+泄漏通过RyR2在家族性肥厚性心肌病相关心肌肌钙蛋白T突变转基因小鼠（TG）模型中的致病作用。β -肾上腺素能刺激TG心肌细胞通过RyR2缺陷诱导舒张Ca2+泄漏。丹trolene和Calmodulin-kinaseII抑制剂可以通过稳定RyR2抑制Ca2+泄漏。这些结果可能提示RyR2的稳定和抑制Ca2+泄漏可能在HCM致死性心律失常的发病机制中起作用。

项目成果

Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker for predicting cardiac events and evaluating the effectiveness of carvedilol treatment in patients with chronic systolic heart failure.

• DOI: 10.1253/circj.cj-11-0537
• 发表时间: 2012
• 期刊: Circulation journal : official journal of the Japanese Circulation Society
• 作者: Takehisa Susa;Shigeki Kobayashi;Takeo Tanaka;Wakako Murakami;Shintaro Akashi;I. Kunitsugu;S. Okuda;M. Doi;Y. Wada;T. Nao;Jutaro Yamada;T. Ueyama;T. Okamura;M. Yano;M. Matsuzaki

Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation.

增强钙调蛋白与 RyR2 的结合可抑制 CPVT 相关突变中的异常 Ca2 释放。

• 发表时间: 2011
• 作者: Masakazu Fukuda;Masafumi Yano;Takayoshi Kato;Akihiro Hino;Takeshi Suetomi;Masahiro Doi;Shinichi Okuda;Shigeki Kobayashi;Yasuhiro Ikeda;Takeshi Yamamoto;Masunori Matsuzaki.
• 通讯作者: Masunori Matsuzaki.

Correcting inter-domain interaction of cardiac ryanodine receptor inhibits aberrant Ca^ release in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy mouse model

纠正心脏兰尼碱受体的域间相互作用抑制心肌肌钙蛋白 T 相关家族性肥厚性心肌病小鼠模型中异常的 Ca^2 释放

• 发表时间: 2012
• 作者: Okuda S;Yano M;Fukuda M;Suetomi T;Hino A;Kato T;Doi M;Kobayashi S;Yamamoto T;Matsuzaki M
• 通讯作者: Matsuzaki M

Mutation-Linked Defective Interdomain Interactions Within Ryanodine Receptor Cause Aberrant Ca2+ Release Leading to Catecholaminergic Polymorphic Ventricular Tachycardia

兰尼碱受体内突变相关的缺陷性域间相互作用导致异常 Ca2 释放，导致儿茶酚胺能多形性室性心动过速

• 发表时间: 2011-08
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Xu X.;Tateishi H.;Okuda S.;Doi M.;Kobayashi S.;Ikeda Y.;Yamamoto T.;Ikemoto N.;Matsuzaki M.
• 通讯作者: Matsuzaki M.

Urinary 8-hydroxy-2′-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure

• DOI: 10.1093/eurjhf/hfq178
• 发表时间: 2011-01-01
• 期刊: EUROPEAN JOURNAL OF HEART FAILURE
• 影响因子: 18.2
• 作者: Kobayashi, Shigeki;Susa, Takehisa;Matsuzaki, Masunori
• 通讯作者: Matsuzaki, Masunori