Development of therapeutic therapy for regression of cardiac hypertrophy in hypertrophic cardiomyopathy

肥厚型心肌病心肌肥厚消退治疗方法的开发

• 批准号: 22659154
• 负责人: YANO Masafumi
• 金额: $ 2.02万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22659154/
• 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; カルシウム動態; 筋小胞体; カルシウム; 心不全; 致死的不整脈; 点突然変異

Hypertrophic cardiomyopathy(HCM) is known to be a myocardial disorder characterized by idiopathic hypertrophy of the left ventricule. In HCM patients, sudden death occurs owing to lethal arrhythmia in young age and diastolic heart failure can be sometimes developed. Medical approach for regression of hypertrophy in HCM patients remains elusive. Here, we hypothesized that diastolic Ca2+ leak through ryanodine receptor(RyR2) might predispose to abnormal hypertrophy in HCM patients. 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, which was found to stabilize RyR2 inhibited Ca2+ leak. These results suggest that stabilization of RyR2 and subsequent inhibition of Ca2+ leak might play a pivotalrole for regression of abnormal hypertrophy in HCM patients.

肥厚型心肌病(HCM)是一种以特发性左心室肥大为特征的心肌疾病。在肥厚型心肌病患者中，年轻时因致命性心律失常而猝死，有时可发展为舒张性心力衰竭。肥厚性心肌病患者肥厚消退的医学方法仍然难以捉摸。在这里，我们假设通过兰尼定受体(RyR2)的舒张期钙离子泄漏可能是肥厚性心肌病患者异常肥厚的易感因素。为了验证这一假设，我们在家族性肥厚型心肌病相关心肌肌钙蛋白T突变的转基因小鼠(TG)模型中研究了RyR2中钙离子泄漏的致病作用。TG心肌细胞通过缺陷RyR2的舒张期钙泄漏是由β-肾上腺素能刺激引起的。丹曲林是一种稳定RyR2的药物，它能抑制钙离子泄漏。这些结果提示，RyR2的稳定和随后的钙泄漏的抑制可能在肥厚性心肌病患者异常肥厚的消退中起关键作用。

项目成果

Increased Affinity of Calmodulin Binding to Cardiac Ryanodine Receptor Corrects the Defective Channel Gating in Failing Hearts

钙调蛋白与心脏兰尼定受体结合的亲和力增加可纠正衰竭心脏中的缺陷通道门控

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

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.

Correction of Defective Calmodulin Binding to Cardiac Ryanodine Receptor Inhibits Aberrant Ca2+ Release in CPVT-associated Mutation

校正有缺陷的钙调蛋白与心脏兰尼定受体的结合抑制 CPVT 相关突变中的异常 Ca2 释放

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

慢性心不全治療ガイドライン;冠動脈疾患下巻

慢性心力衰竭治疗指南；冠状动脉疾病第2卷

• 发表时间: 2011
• 作者: 奥田真一;矢野雅文
• 通讯作者: 矢野雅文

Polymorphic Ventricular Tachycardia Is Caused by Mutation-Linked Defective Conformational Regulation of the Ryanodine Receptor.

多形性室性心动过速是由与突变相关的瑞尼丁受体构象调节缺陷引起的。

• 发表时间: 2010
• 期刊: Circulation Research
• 影响因子: 20.1
• 作者: Okada S;Kozuka C;Masuzaki H;Yasue S;Ishii-Yonemoto T;Tanaka T;Yamamoto Y;Noguchi M;Kusakabe T;Tomita T;Fujikura J;Ebihara K;Hosoda K;Sakaue H;Kobori H;Ham M;Lee YS;Kim JB;Saito Y;Nakao K;中島淳;Hitoshi Uchinoumi
• 通讯作者: Hitoshi Uchinoumi