Molecular Pathogenesis of Cardiac Failure due to Gene Abnormalities

基因异常导致心力衰竭的分子发病机制

• 批准号: 13470142
• 负责人: KIMURA Akinori
• 金额: $ 6.27万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470142/
• 关键词: Gene; Cardiac Failure; Cardimyopathy; Stretch Response; Z-disk; Hypertension; Polymorphism; Mutation; 肥大型心筋症; 拡張型心筋症; Cypher変異; PKC; カルサルチン; Tcap; カベオリン; 遺伝子変異; トランスジェニックマウス; タイチン; MLP; ミオシン脱リン酸化; 心肥大; テレトニン

Idiopathic cardiomyopathy was defined as cardiomyopathy of unknown etiology. Recent molecular genetic analysis has revealed that gene abnormalities are involved in the etiology and/or pathogenesis of idiopathic cardiomyopathy. As well, hypertensive cardiomyopathy may also be relevant to the gene abnormalities in the pathogenesis. In this study, we have revealed that mutations in the genes for Z-disk elements, TTN, TCAP, MLP, and Cypher, cause cardiomyopathy. Functional studies of the mutations in each disease gene have shown that hypertrophic cardiomyopathy-related mutations increase the binding ability of the Z-disk elements, whereas dilated cardiomyopathy-related mutations decrease the binding ability. It also has been demonstrated that the Z-disk plays a key role in the stretch-sensing of cardiomyocytes from the analysis of a well known dilated cardiomyopathy model of MLP deficient mice. It was suggested that the stretch-response involved phosphorylation of Z-disk proteins, because the Z-disk protein abnormalities were predicted to change the distribution of calcineurin and PKC. In addition, Ca-sensitization and -desensitization played a crucial role in the pathogenesis of cardiac hypertrophy and failure, respectively. Analysis of hypertrophied and dilated hearts from M21-transgenic mice and Dah1 salt-sensitive hypertensive rats by DNA-chip technology showed that a number of genes were involved in the pathogenesis of cardiomyopathy. One of the new genes identified to be differentially expressed in the cardiac hypertrophy and failure is a growth factor-like gene specifically expressed in the heart. We identified a mutation in that growth factor-like gene that was associated with hypertensive cardiomyopathy.

特发性心肌病定义为病因不明的心肌病。最近的分子遗传学分析表明，基因异常参与了特发性心肌病的病因和/或发病机制。高血压性心肌病的发生也可能与基因异常有关。在这项研究中，我们发现，基因突变的Z盘元件，TTN，TCAP，MLP，和Cypher，导致心肌病。对每种疾病基因突变的功能研究表明，肥厚型心肌病相关突变增加了Z盘元件的结合能力，而扩张型心肌病相关突变降低了结合能力。通过对MLP缺陷小鼠的扩张型心肌病模型的分析，也证明了Z盘在心肌细胞的牵张感知中起着关键作用。这表明牵张反应涉及Z盘蛋白的磷酸化，因为Z盘蛋白异常被预测改变钙调磷酸酶和PKC的分布。此外，钙增敏和钙脱敏分别在心肌肥厚和心力衰竭的发病机制中起着至关重要的作用。利用DNA芯片技术对M21转基因小鼠和Dah 1盐敏感性高血压大鼠的肥大和扩张心脏进行分析，发现心肌病的发病机制涉及多个基因。新发现的在心肌肥厚和心力衰竭中差异表达的基因之一是在心脏中特异表达的生长因子样基因。我们在生长因子样基因中发现了一个与高血压性心肌病相关的突变。

项目成果

Kimura A, Itoh-Satoh M, Hayashi T, Takahashi M, Arimura T: "Molecular etiology of idiopathic cardiomyopathy in Asian populations."J Cardiol.. 37. S139-S146 (2002)

Kimura A、Itoh-Satoh M、Hayashi T、Takahashi M、Arimura T：“亚洲人群特发性心肌病的分子病因学”。J Cardiol.. 37. S139-S146 (2002)

Knoll R, Hoshijima M, Hoffmann HM, Person V, Lorenzen-Schmidt I, Bang M-L, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork J, Jeffrey H, Omens J, Andrew D, McCulloch A, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheless HP,

Knoll R、Hoshijima M、Hoffmann HM、Person V、Lorenzen-Schmidt I、Bang M-L、Hayashi T、Shiga N、Yasukawa H、Schaper W、McKenna W、Yokoyama M、Schork J、Jeffrey H、Omens J、Andrew D、

1toh-Satoh M, Hayashi T, Nishi H, et al.: "Titin mutations as the molecular basis for dilated cardiomyopathy"Biochem. Biophys. Res. Commun.. 291. 385-393 (2002)

1toh-Satoh M、Hayashi T、Nishi H 等人：“Titin 突变是扩张型心肌病的分子基础”Biochem。

Ogimoto A, et al.: "17-year follow-up study of a patient with obstructive hypertrophic cardiomyopathy with a deletion mutation in the cardiac myosin binding protein C gene."Circ J.. 68. 174-177 (2004)

Ogimoto A 等人：“对一名患有心肌肌球蛋白结合蛋白 C 基因缺失突变的阻塞性肥厚型心肌病患者进行的 17 年随访研究。”Circ J.. 68. 174-177 (2004)

Arimura T, Suematsu N, Zhou YB, et al.: "Identification, characterization and functional analysis of heart-specific myosin light chain phoshatase small subunit"J. Biol. Chem.. 276. 6073-6082 (2001)

Arimura T，Suematsu N，Zhou YB，等：“心脏特异性肌球蛋白轻链磷酸酶小亚基的鉴定、表征和功能分析”J。