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

• Project/Area Number: 16390219
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KIMURA Akinori Tokyo Medical and Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (60161551)
• Co-Investigator(Kenkyū-buntansha): 安波 道郎 東京医科歯科大学, 大学院・疾患生命科学研究部, 助教授 (80244127) ; 沢辺 元司 東京都老人医療センター, 剖検病理科, 医長 (30196331)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥13,900,000 (Direct Cost: ¥13,900,000); Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000); Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000); Fiscal Year 2004: ¥5,100,000 (Direct Cost: ¥5,100,000)
• Keywords: 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

Research Abstract

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.

Research Products

• [Journal Article] Human cardiac ryanodine receptor mutations in ion channel disorders in Japan (2007)
  • Author(s): Aizawa Y, Mitsuma W, Ikrar T, Komura S, Hanawa H, Miyajima S, Miyoshi F, Kobayashi Y, Chinushi M, Kimura A, Hiraoka M, Aizawa Y
  • Journal Title: Int J Cardiol 116(2) Pages: 263-265
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy (2007)
  • Author(s): Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Itoh-Satoh M, Bonne G, Schwartz K, Kimura A
  • Journal Title: Biochem Biophys Res Commun 46(6) Pages: 285-289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human cardiac ryanodine receptor mutations in ion channel disorders in Japan. (2007)
  • Author(s): Aizawa Y, Mitsuma W, Briar T, Komura S, Hanawa H, Miyajima S, Miyoshi F, Kobayashi Y, Chinushi M, Kimura A, Hiraoka M, Aizawa Y
  • Journal Title: Int J Cardiol 116(2) Pages: 263-265
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy. (2007)
  • Author(s): Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Itoh-Satoh M, Bonne G, Schwartz K, Kimura A
  • Journal Title: Biochem Biophys Res Commun 357(1) Pages: 162-167
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human cardiac ryanodine receptor mutations in ion channel disorders in Japan (2007)
  • Author(s): Aizawa Y, Mitsuma W, Ikrar T, Komura S, Hanawa H, Miyajima S, Miyoshi F, Kobayasi Y, Chinushi M, Kimura A, Hiraoka M, Aizawa Y
  • Journal Title: Int J Cardiol 116(2) Pages: 263-265
• [Journal Article] Structural analysis of four and half LIM protein (2007)
  • Author(s): Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Itoh-Satoh M, Bonne G, Schwartz K, Kimura A
  • Journal Title: Biochem Biophys Res Commun (In press)
• [Journal Article] alphaB-crystallin in mutation in dilated cardiomyopathy (2006)
  • Author(s): Inagaki N, Hayashi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K, Chikamori T, Yamashina A, Kimura A
  • Journal Title: Biochem Biophys Res Commun 342(2) Pages: 379-386
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Direct determination of SNP haplotype of NFKBIL1 promoter polymorphism by DNA conformation analysis and its application to association study of chronic inflammatory diseases (2006)
  • Author(s): Shibata H, Yasunami M, Obuchi N, Takahashi M, Kobayashi Y, Numano F, Kimura A
  • Journal Title: Hum Immunol 67(4-5) Pages: 363-373
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] AlphaB-crystallin in mutation in dilated cardiomyopathy. (2006)
  • Author(s): Inagaki N, Hayashi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K, Chikamori T, Yamashina A, Kimura A
  • Journal Title: Biochem Biophys Res Commun 342(2) Pages: 379-386
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Direct determination of SNP haplotype of NFKBIL1 promoter polymorphism by DNA conformation analysis and its application to association study of chronic inflammatory diseases. (2006)
  • Author(s): Shibata H, Yasunami M, Obuchi N, Takahashi M, Kobayashi Y, Numano F, Kimura A
  • Journal Title: Hum Immunol 67(4.5) Pages: 363-373
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Direct determination of SNP haplotype of NFKBIL1 promoter polymorphism by DNA conformation analysis and its application to association study of chronic inflammatory diseases (2006)
  • Author(s): Shibata H, Yasunami M, Obuchi N, Takahashi M, Kobayashi Y, Numano F, Kimura A
  • Journal Title: Human Immunology 67(4-5) Pages: 363-373
• [Journal Article] Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy (2006)
  • Author(s): Matusmoto Y, Hayashi T, Inagaki N, Takahashi M, Hiroi S, Nakamura T, Arimura T, Nakamura K, Ashizawa N, Yasunami M, Ohe T, Yano K, Kimura A
  • Journal Title: J.Muscle Res.Cell Motil (印刷中)
• [Journal Article] αB-crystallin in dilated cardiomyopathy (2006)
  • Author(s): Inagaki N, Hayahsi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K, Chikamori T, Yamashina A, Kimura A
  • Journal Title: Biochem Biophys Res Commun (印刷中)
• [Journal Article] A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in Japanese patient with catecholaminergic polymorphic ventricular tachycardia (2005)
  • Author(s): Aizawa Y, Ueda K, Komura S, Washizuka T, Chinushi M, Inagaki N, Matsumoto Y, Hayashi T, Takahashi M, Nakano N, Yasunami M, Kimura A, Hiraoka M, Aizawa Y
  • Journal Title: Int J Cardiol 99(2) Pages: 343-345
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spontaneous T wave alterans in a patient with Brugada syndrome-responses to intravenous administration of class I antiarrhythmic drug, glucose tolerance test, and atrial pacing (2005)
  • Author(s): Nishizaki M, Fujii H, Sakurada H, Kimura A, Hiraoka M
  • Journal Title: J. Cardiovasc Electrophysiol 16 Pages: 217-220
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein C gene (2005)
  • Author(s): Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamazaki N, Furuno T, Takata J, Nishinaga M, Kimura A, Doi YL
  • Journal Title: J Am Coll Cardiol 46(9) Pages: 1737-1743
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus associated dilated cardiomyopathy (2005)
  • Author(s): Shichi D, Kikkawa FE, Ota M, Katsuyama Y, Kimura A, Matsumori A, Kulsky JK, Naruse KT, Inoko H
  • Journal Title: Tissue Antigens 66(3) Pages: 200-208
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy (2005)
  • Author(s): Matsumoto Y, Hayashi T, Inagaki N, Takahashi M, Hiroi S, Nakamura T, Arimura T, Nakamura K, Ashizawa N, Yasunami M, Ohe T, Yano K, Kimura A
  • Journal Title: J Muscle Res Cell Motil 26(6-8) Pages: 367-374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spontaneous T wave alterans in a patient with Brugada syndrome--responses to intravenous administration of class I antiarrhythmic drug, glucose tolerance test, and atrial pacing. (2005)
  • Author(s): Nishizaki M, Fujii H, Sakurada H, Kimura A, Hiraoka M
  • Journal Title: J Cardiovasc Electrophysiol 16 Pages: 217-220
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein C gene. (2005)
  • Author(s): Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamazaki N, Furuno T, Takata J, Nishinaga M, Kimura A, Doi YL
  • Journal Title: J Am Coll Cardiol 46(9) Pages: 1727-1743
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus associated dilated cardiomyopathy. (2005)
  • Author(s): Shichi D, Kikkawa FE, Ota M, Katsuyama Y, Kimura A, Matsumori A, Kulsky JK, Naruse KT, Inoko H
  • Journal Title: Tissue Antigens 66(3) Pages: 200-208
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy. (2005)
  • Author(s): Matsumoto Y, Hayashi T, Inagaki N, Takahashi M, Hiroi S, Nakamura T, Arimura T, Nakamura K, Ashizawa N, Yasunami M, Ohe T, Yano K, Kimura A
  • Journal Title: J Muscle Res Cell Motil 26(6.8) Pages: 367-374
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein C gene (2005)
  • Author(s): Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamazaki N, Furuno T, Takata J, Nishinaga M, Kimura A, Doi YL
  • Journal Title: J Am Coll Cardiol 46 Pages: 1737-1743
• [Journal Article] The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus associated dilated cardiomyopathy (2005)
  • Author(s): Shichi D, Kikkawa FE, Ota M, Katsuyama Y, Kimura A, MatsumoriA, Kulsky JK, Naruse KT, Inoko H
  • Journal Title: Tissue Antigens 66 Pages: 200-208
• [Journal Article] Functional analysis of titin/connectin N2-B mutations found in cardiomyopat (2005)
  • Author(s): Matsuomoto Y, Hayashi T, Inagaki N, Takahashi M, Hiroi S, Nakamura T, Arimura T, Nakamura K, Ashizawa N, Yasunami M, Ohe T, Yano A, Kimura A
  • Journal Title: J.Muscle Res.Cell Motil (In press)
• [Journal Article] Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia (2004)
  • Author(s): Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesata Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A
  • Journal Title: J Biol Chem 279(26) Pages: 27194-27198
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Unexpected mexiletine responses of a mutant cardiac Na+ channel implicate the selectivity filter as a structural determinant of antiarrhythmic drug access (2004)
  • Author(s): Sasaki K, Makita N, Sunami A, Sakurada H, Shirai N, Yokoi H, Kimura A, Tohse N, Hiraoka M, Kitabatake A
  • Journal Title: Mol Pharmacol 66 Pages: 330-336
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking (2004)
  • Author(s): 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
  • Journal Title: FEBS Lett 574(1-3) Pages: 145-150
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2 : additional amino acids generated by frameshift cause accelerated inactivation (2004)
  • Author(s): Sasano T, Ueda K, Orikabe M, Hirano Y, Kawano S, Yasunami M, Isobe M, Kimura A, Hiraoka M
  • Journal Title: J Mol Cell Cardiol 37(6) Pages: 1205-1211
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TCAP mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy (2004)
  • Author(s): Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki, N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Cho BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A
  • Journal Title: J Am Col Cardiol 44(11) Pages: 2192-2201
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. (2004)
  • Author(s): Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesata Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A
  • Journal Title: J Biol Chem 279(26) Pages: 27194-27198
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking (2004)
  • Author(s): 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
  • Journal Title: FEBS Lett 574(1.3) Pages: 145-150
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation. (2004)
  • Author(s): Sasano T, Ueda K, Orikabe M, Hirano Y, Kawano S, Yasunami M, Isobe M, Kimura A, Hiraoka M
  • Journal Title: J Mol Cell Cardiol 37(6) Pages: 1205-1211
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TCAP mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy (2004)
  • Author(s): Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki, N, Takahashi M, Hori H, Yathimami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Cho BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A
  • Journal Title: J AM Col Cardiol 44(11) Pages: 2192-2201
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C (2004)
  • Author(s): Arimura T, Hayashi T, Terada H, Lee SY, Zhou Q, Takahashi M, Ueda K, Nouchi T, Hohda S, Sibutani M, Hirose M, Chen J, Park JE, Yasunami M, Hayashi H, Kimura A
  • Journal Title: J.Biol.Chem. 279 Pages: 6746-6752
• [Journal Article] TCAP mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy (2004)
  • Author(s): Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki, N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Cho BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A
  • Journal Title: J.Am.Col.Cardiol 44 Pages: 2192-2201
• [Journal Article] The role of a common TNNT2 polymorphism in cardiac hypertrophy (2004)
  • Author(s): Komamura K, Iwai N, Kokame K, Yasumura Y, Kim J, Yamagishi M, Norisaki T, Kimura A, Tomoike H, Kitakaze M, Miyatake K
  • Journal Title: J.Hum.Genet 49 Pages: 129-133
  • NAID: 10012891095
• [Journal Article] Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia (2004)
  • Author(s): Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesata Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A
  • Journal Title: J.Biol.Chem. 279 Pages: 27194-27198
• [Journal Article] Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking. (2004)
  • Author(s): Aizawa Y, Ueda K, Wu LM, Inagaki M, Hayashi T, Takahashi M, Ohta M, Kawano S, Hirano Y, Yasunami M, Aizawa Y, Kimura A, Hiraoka M
  • Journal Title: FEBS Lett 574 Pages: 145-150
• [Journal Article] Novel C-terminus frameshift mutation. 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation (2004)
  • Author(s): Sasano T, Ueda K, Orikabe M, Hirano Y, Kawano S, Yasunami M, Isobe M, Kimura A, Hiraoka M
  • Journal Title: J.Mol.Cell.Cardiol. 37 Pages: 1205-1211