2012 Fiscal Year Final Research Report
Development of strategies for handling heart failure based on the molecular pathogenesis of cardiomyopathy
| Project/Area Number |
22390157
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KIMURA Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
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| Project Period (FY) |
2010 – 2012
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| Keywords | 遺伝学 / 遺伝子 / ゲノム / 循環器・高血圧 |
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| Research Abstract |
Identification of novel disease genes for cardiomyopathy and functional analyses of various cardiomyopathy-associated mutations were performed. We identified novel disease genes for cardiomyopathy, such that CARP mutations in hypertrophic cardiomyopathy, nebulette mutations and BAG3 in dilated cardiomyopathy,and myopalladin mutations in hypertrophic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. Functional studies of the cardiomyopathy-associated mutations revealed that CARP mutations increased binding to titin and enhance the nuclear translocation. Nebulette mutations impaired sarcomerogenesis and BAG3 mutations increased susceptibility to stress-induced apoptosis. Myopalladin mutations impaired sarcomerogenesis. In addition, we revealed a molecular mechanism for calcium sensitivity of cardiac contraction by heart-specific small subunit of myosin phosphatase, M21.Moreover, it was demonstrated that a chemical enhancing calcium sensitivity of muscle contraction, SCH00013, could prolong the survival prognosis of dilated cardiomyopathy in lamina/C mutation knock-in mice, suggesting that the regulation of calcium sensitivity is a novel therapeutic/preventive strategy for heart failure associated with cardiomyopathy
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[Journal Article] Novel SCN3B mutation associated with Brugada syndrome affects intracellular trafficking and function of Nav1.52013
Author(s)
Ishikawa T, Takahashi N, Ohno S, Sakurada H, Nakamura K, On YK, Park JE, Makiyama T, Horie M, Arimura T, Makita N, Kimura A
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Journal Title
Circ J
Volume: 77(4)
Pages: 959-967
Peer Reviewed
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[Journal Article] Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy2012
Author(s)
Otsuka H, #Arimura T, Abe T, Kawai H, Aizawa Y, Kubo T, Kitaoka H, Nakamura H, Nakamura K, Okamoto H, Ichida F, Ayusawa M, Nunoda S, Isobe M, Matsuzaki M, Doi YL, Fukuda K, Sasaoka T, Izumi T, Ashizawa N, Kimura A
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Journal Title
Circ J
Volume: 76(2)
Pages: 453-461
Peer Reviewed
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[Journal Article] Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations2012
Author(s)
Purevjav E, Arimura T, Augustin S, Huby A-C, Takagi K, Nunoda S, Kearney DL, Taylor MD, Terasaki F, Bos JM, Ommen SR, Shibata H, Takahashi M, Itoh-Satoh M, McKenna W, Murphy RT, Labeit S, Yamanaka Y, Machida N, Park JE, Alexander PMA, Weintraub RG, Kitaura Y, Ackerman MJ, Kimura A, Towbin JA
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Journal Title
Hum Mol Genet
Volume: 21(9)
Pages: 2039-2053
Peer Reviewed
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[Journal Article] Similarities and differences in genetic and clinical characteristics between early repolarization syndrome and Brugada syndrome2012
Author(s)
Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Nagao S, Yagihara N, Takehara N, Kawamura Y, Sato A, Okamura K, Sato M, Hosaka Y, Fukae S, Chinushi M, Oda H, Okabe H, Kimura A, Maemura K, Watanabe I, Kamakura S, Aizawa Y, Shimizu W, Makita N
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 5(2)
Pages: e60-e61
Peer Reviewed
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[Journal Article] Clinical characteristics and risk of arrhythmia recurrences in patients with idiopathic ventricular fibrillation associated with early repolarization2012
Author(s)
Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Makiyama T, Nagao S, Yagihara N, Takehara N, Kawamura Y, Sato A, Okamura K, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Shimizu W, Makita N
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Journal Title
Int J Cardiol
Volume: 159(3)
Pages: 238-240
Peer Reviewed
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[Journal Article] Loss-of-function of hNav1.5 by ZASP1-D117N associated with intraventricular conduction disturbances in left ventricular noncompaction2012
Author(s)
Xi Y, Ai T, De Lange E, Li Z, Wu G, Brunelli L, Kyle WB, Cheng J, Ackerman MJ, Kimura A, Weiss JN, Qu Z, Kim JJ, Faulkner G, Vatta M
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 5(5)
Pages: 1017-1026
Peer Reviewed
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[Journal Article] Dilated phase of hypertrophic cardiomyopathy caused by two different sarcomere mutations, treated with surgical left ventricular reconstruction and cardiac resynchronization therapy with a defibrillator2012
Author(s)
Sato A, Sakamoto N, Ando K, Kaneshiro T, Uekita H, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Sato M, Tamagawa K, Arimura T, Kimura A, Takeishi Y
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Journal Title
Intern Med
Volume: 51(18)
Pages: 2559-2564
Peer Reviewed
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[Journal Article] A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.52012
Author(s)
Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, Schwartz PJ, On YK, Park JE, Nakamura K, Hiraoka M, Nakazawa K, Sakurada H, Arimura T, Makita N, Kimura A
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 5(6)
Pages: 1098-1107
Peer Reviewed
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[Journal Article] Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy2011
Author(s)
Kubo T, Kitaoka H, Okawa M, Baba Y,Hirota T,Hayato K, Yamasaki N,Matsumura Y, Otsuka H,Arimura T,Kimura A, Doi YL
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Journal Title
Circ J
Volume: 75(11)
Pages: 2654-2659
Peer Reviewed
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[Journal Article] Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization2011
Author(s)
Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Nagao S,Yagihara N, Takehara N, Kawamura Y,Sato A, Okamura K, Sato M, Hosaka Y,Fukae S, Chinushi M, Oda H, Okabe H, Kimura A, Maemura K, Watanabe I,Kamakura S,Aizawa Y, Shimizu W, Makita N
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 4(6)
Pages: 874-881
Peer Reviewed
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[Journal Article] A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy2010
Author(s)
Li Z, Ai T, Samani K, Xi Y, Tzeng HP,Xie M,Wu S, Ge S, Taylor MD, Dong JW,Cheng J, Ackerman MJ, Kimura A, Sinagra G, Brunelli L, Faulkner G, Vatta M
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 3(6)
Pages: 646-656
Peer Reviewed
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[Journal Article] Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis2010
Author(s)
Purevjav E, Varela J, Morgado M,Kearney DL, Li H, Taylor MD, Arimura T, Moncman CL, McKenna W, Labeit S, Vatta M, Bowles NE, Kimura A, Boriek AM, Towbin JA
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Journal Title
J Am Coll Cardiol
Volume: 56(18)
Pages: 1493-1502
Peer Reviewed
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[Journal Article] A ZASP missense mutation, S196L,leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy2010
Author(s)
Li Z, Ai T, Samani K, Xi Y, Tzeng HP,Xie M,Wu S, Ge S, Taylor MD, Dong JW,Cheng J, Ackerman MJ, Kimura A, Sinagra G, Brunelli L, Faulkner G,Vatta M
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 3(6)
Pages: 646-656
Peer Reviewed
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[Journal Article] Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations
Author(s)
Arimura T, Onoue K, Takahashi-Tanaka Y, Ishikawa T, Kuwahara M, Setou M, Shigenbu S, Yamaguchi K, Bertrand AT, Machida N, Takayama K, Fukusato M, Tanaka R, Somekawa T, Nakano T, Yamane Y, Kuba K, Imai Y, Saito N, Bonne G, Kimura A
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Journal Title
Cardiovasc Res
Volume: (in press)
DOI
Peer Reviewed
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