Exploration of the pathogenic mechanisms of inherited cardiomyopathies caused by cardiac troponin T mutations

心肌肌钙蛋白T突变所致遗传性心肌病发病机制探讨

• 批准号: 15300136
• 负责人: MORIMOTO Sachio
• 金额: $ 9.41万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15300136/
• 关键词: Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Ristrected cardiomyopathy; Troponin; Gene mutation; Knock-in mouse; Calcium sensitivity; Mouse model for human diseases; 遺伝子突然変異; 心筋症; 遺伝子改変; モデル動物; ノックアウトマウス; サルコメア病

Dilated cardiomyopathy (DCM) represents a heterogeneous group of inherited and acquired disorders characterized by cardiac dilation and systolic dysfunction, which leads to heart failure and sudden death, being the primary indication for cardiac transplantation. DCM-causing mutations have been found in the genes for cytoskeletal and sarcomeric proteins. We have created a knock-in mouse model for DCM caused by the deletion mutation ΔK210 in cardiac troponin T. Mutant mice developed enlarged hearts and showed a high incidence of sudden death with no sign of heart failure. Histological examination of cardiac sections from mutant mice showed a significant dilation of both ventricles with mild to moderate fibrosis. Echocardiography measurements showed that the ejection fraction of left ventricle was significantly smaller in mutant mice than in wild-type mice, indicating a reduced systolic function of mutant mice hearts in vivo. Isolated working heart preparations from mutant mice showed a decreased dP/dt_<max> with no significant change in dP/dt_<min>. However, no significant reduction in cardiac output was found in mutant mice, suggesting a complete compensation by ventricular enlargement. Studies using a telemetry system for ECG recording strongly suggested that the deletion mutation ΔK210 in cardiac troponin T results in a high incidence of sudden death due to a cardiac electrophysiological abnormality despite well-compensated mechanical performance of the heart.

扩张型心肌病（Dilated cardiomyopathy，DCM）是一组以心脏扩张和收缩功能障碍为特征的遗传性和获得性疾病，其导致心力衰竭和猝死，是心脏移植的主要指征。已在细胞骨架蛋白和肌节蛋白的基因中发现了导致DCM的突变。我们已经建立了一个基因敲入小鼠模型，用于心肌肌钙蛋白T缺失突变ΔK210引起的DCM。突变小鼠的心脏增大，猝死的发生率很高，没有心力衰竭的迹象。突变小鼠心脏切片的组织学检查显示两个心室显著扩张，伴有轻度至中度纤维化。超声心动图测量显示，突变小鼠的左心室射血分数显著小于野生型小鼠，表明突变小鼠心脏在体内的收缩功能降低。从突变小鼠分离的工作心脏制备物显示dP/dt_降低<max>，而dP/dt_无显著变化<min>。然而，在突变小鼠中没有发现心输出量的显著减少，表明心室扩大的完全补偿。使用遥测系统进行ECG记录的研究强烈表明，尽管心脏具有良好的代偿性机械性能，但心肌肌钙蛋白T中的缺失突变ΔK210导致心脏电生理异常导致猝死的发生率很高。

项目成果

Troponin I inhibitory peptide suppresses the force generation in smooth muscle by directly interfering the cross-bridge formation.

肌钙蛋白 I 抑制肽通过直接干扰跨桥形成来抑制平滑肌中力的产生。

• 发表时间: 2003
• 期刊: Biochem.Biophys.Res.Commun. 307(2)
• 作者: Watanabe;M.;Yoshino;Y.;Morimoto;S.
• 通讯作者: S.

Several aspects of Ca-regulatory mechanisms linked to Troponin

与肌钙蛋白相关的 Ca 调节机制的几个方面

• 发表时间: 2003
• 期刊: Adv.Exp.Med.Biol. 538
• 作者: Ohno T;Sakurai M;I.Ohtsuki et al.
• 通讯作者: I.Ohtsuki et al.

SCH00013, a novel Ca(2+) sensitizer with positive inotropic and no chronotropic action in heart failure.

SCH00013，一种新型 Ca(2) 敏化剂，对心力衰竭具有正性肌力作用，但无变时作用。

• 发表时间: 2005
• 期刊: Journal of Pharmacological Sciences
• 影响因子: 3.5
• 作者: N. Tadano;S. Morimoto;A. Yoshimura;M. Miura;K. Yoshioka;M. Sakato;I. Ohtsuki;Y. Miwa;F. Takahashi;T. Sasaguri
• 通讯作者: T. Sasaguri

Qun-Wei Lu: "Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca^<2+>-desensitization"J.Mol.Cell.Cardiol.. 35(12). 1421-1427 (2003)

Qun-Wei Lu：“扩张型心肌病中发现的心肌肌钙蛋白T突变R141W稳定了肌钙蛋白T-原肌球蛋白相互作用并导致Ca^2-脱敏”J.Mol.Cell.Cardiol.. 35(12)。

モデル動物の作製と維持

模型动物的创建和维护

• 发表时间: 2004
• 作者: 小澤哲夫;北島 勲
• 通讯作者: 北島 勲