Investigation of the molecular mechanisms of cardiac failure focusing on the Z-disc abnormalities

以Z盘异常为中心的心力衰竭分子机制研究

• 批准号: 16390219
• 负责人: KIMURA Akinori
• 金额: $ 8.9万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390219/
• 关键词: hypertrophic cardiomyopathy; dilated cardiomyopathy; mutation; pathogenesis; calcium sensitivity; stretch response; metabolic stress response; myosin light chain; 心不全; 原因遺伝子; 機能連関; Z帯; 遺伝子変異; 高血圧性心筋症; TCAP; 心筋リモデリング

Heart failure is a disease condition defined by insufficient cardiac output required for oxygen supply. Causes of the most severe heart failure include hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). We have identified disease genes for HCM and/or DCM and suggested the linkage between the heart failure, and abnormality in Z-disc function. In this study, we aimed to identify the Z-disc abnormalities associated with heart failure and to reveal the molecular mechanisms of heart failure caused by the Z-disc abnormalities as well as to obtain a strategy to suppress the abnormal function of Z-disc. Main topics were as follows. (1) TCAP mutations were found in the patients with HCM and mutations in TCAP, CRYAB and FHL2 were, found in the patients with DCM. In addition MYPN mutation was found in restrictive cardiomyopathy, (RCM). TCAP, CRYAB, FHL2 and MYPN encoded components of Z-band or I-band, further supporting the pathological roles of abnormalities in the Z-I band function. (2) TTN mutations impaired interaction with FHL2 and CRYAB, suggesting the interaction of TTN with FHL2 and CRYAB was important for cardiac muscle function. (3) MYPN mutation found in RCM impaired formation of myofibrils in rat cardiomyocytes, suggesting the functional role of MYPN in cardiac sarcomerogenesis. (4) Cypher/ZASP bound to a metabolic enzyme and Cyper/ZASP mutations disrupted this interaction, and the metabolic enzyme was found to localized into Z-I band region upon stress to cardiomyocytes. These findings suggested a novel function of Z-band. (5) M21, a small inhibitory subunit of PP1M, increased calcium sensitivity of cardiac muscle contraction, and M21-overexpressing transgenic mice showed sudden death and cardiac hypertrophy accompanied by myocyte-disarrays, which were closely similar to the clinical observations in HCM. The M21-transgenic mice would be a good animal model for HCM and indicated that the increased calcium sensitivity was the cause of HCM.

心力衰竭是一种由氧供应所需的心输出量不足定义的疾病。最严重的心力衰竭的原因包括肥厚型心肌病（HCM）和扩张型心肌病（DCM）。我们已经确定了HCM和/或DCM的疾病基因，并提出了心力衰竭和Z盘功能异常之间的联系。本研究的目的是鉴定与心力衰竭相关的Z盘异常，揭示Z盘异常导致心力衰竭的分子机制，并获得抑制Z盘异常功能的策略。主要议题如下。(1)HCM患者中存在TCAP突变，DCM患者中存在TCAP、FHL 2和FAB突变。限制性心肌病（RCM）中也发现MYPN突变。TCAP、FHL 2和MYPN编码Z带或I带的组分，进一步支持Z-I带功能异常的病理作用。(2)TTN突变削弱了与FHL 2和FHLAB的相互作用，表明TTN与FHL 2和FHLAB的相互作用对心肌功能很重要。(3)在RCM中发现的MYPN突变损害了大鼠心肌细胞中肌原纤维的形成，表明MYPN在心脏肌角化中的功能作用。(4)Cypher/ZASP与代谢酶结合，Cyper/ZASP突变破坏了这种相互作用，并且发现代谢酶在心肌细胞应激时定位于Z-I带区域。这些发现提示了Z波段的一种新功能。(5)M21是PP 1 M的一个抑制性小亚基，增加心肌收缩的钙敏感性，M21过表达转基因小鼠表现出猝死和心肌肥大，伴有心肌细胞排列紊乱，这与HCM的临床观察结果非常相似。M21转基因小鼠是一种良好的HCM动物模型，提示钙敏感性增加是HCM的原因。

项目成果

Direct determination of SNP haplotype of NFKBIL1 promoter polymorphism by DNA conformation analysis and its application to association study of chronic inflammatory diseases

DNA构象分析直接测定NFKBIL1启动子多态性SNP单倍型及其在慢性炎症疾病关联研究中的应用

• 发表时间: 2006
• 期刊: Hum Immunol 67(4-5)
• 作者: Shibata H;Yasunami M;Obuchi N;Takahashi M;Kobayashi Y;Numano F;Kimura A
• 通讯作者: Kimura A

The role of a common TNNT2 polymorphism in cardiac hypertrophy

• DOI: 10.1007/s10038-003-0121-4
• 发表时间: 2004-03-01
• 期刊: JOURNAL OF HUMAN GENETICS
• 影响因子: 3.5
• 作者: Komamura, K;Iwai, N;Miyatake, K
• 通讯作者: Miyatake, K

Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy

• DOI: 10.1016/j.bbrc.2007.03.128
• 发表时间: 2007-05-25
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Arimura, Takuro;Hayashi, Takeharu;Kimura, Akinori
• 通讯作者: Kimura, Akinori

alphaB-crystallin in mutation in dilated cardiomyopathy

扩张型心肌病中的αB-晶状体蛋白突变

• 发表时间: 2006
• 期刊: Biochem Biophys Res Commun 342(2)
• 作者: Inagaki N;Hayashi T;Arimura T;Koga Y;Takahashi M;Shibata H;Teraoka K;Chikamori T;Yamashina A;Kimura A
• 通讯作者: Kimura A

Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking

截短的 KCNQ1 突变体 A178fs/105 与野生型形成异源多聚体通道，由于运输而导致显性失活抑制

• 发表时间: 2004
• 期刊: FEBS Lett 574
• 作者: Aizawa Y;Ueda K;Wu LM;Inagaki N;Hayashi T;Takahashi M;Ohta M;Kawano S;Hirano Y;Yasunami M;Aizawa Y;Kimura A;Hiraoka M
• 通讯作者: Hiraoka M