心筋代謝調節におけるmicroRNAの役割とその制御機構の解明

2009 Fiscal Year Annual Research Report

• Project/Area Number: 20590864
• Research Institution: Kyoto University
• Principal Investigator: 尾野 亘 Kyoto University, 医学研究科, 助教 (00359275)
• Keywords: microRNA / ATP / ミトコンドリア / 心筋

Research Abstract

miRNAは、蛋白情報を持たない小分子RNAで、遺伝子転写後の発現制御を行っている。miRNAの研究は現在、もっとも注目されている分野のひとつである。
本研究においては、分子生物学的手法を用いてmiRNAによる心筋代謝調節遺伝子制御機構を検討する。網羅的アッセイシステムによる新たな標的miRNAの解明の研究計画においては、心肥大から心不全へ移行する動物モデルにおいて、miR-15bクラスターが心肥大から心不全にいたる際に、特異的に発現上昇することを認めた。in vitroにおいてこのmiR-15bがミトコンドリア内膜に存在する蛋白であるADP-ribosylation factor-like2 (Ar12)をターゲットとし、過剰発現させたときに細胞内ATPを減少させることを確認した。さらに、miR-15bクラスターを阻害するデコイ遺伝子を作成し、心筋細胞に発現させたところ、内因性のmiR-15bが減少し、細胞のATPが上昇した。電子顕微鏡による解析においても、このmiR-15bあるいはAr12に対するsiRNA発現により、ミトコンドリアの形態が変化することを確認した。また、心筋の構造蛋白であるミオシン重鎖遺伝子の発現変化を引き起こすmiRNAも網羅的に解析した。miR-27aが、甲状腺ホルモンの影響下にミオシン重鎖遺伝子の発現に影響を及ぼすことを確認した。さらに詳細なメカニズムを検討中である。さらに、高脂肪食負荷を行ったマウスにおいて心臓でのmiRNAのマイクロアレイ解析を行った。高脂肪食のみで発現の増加しているmiRNAについて、in situ hybridization法により発現の局在を検討中であり、その機能解析を続けている。

Research Products

• [Journal Article] MicroRNA-15b modulates cellular ATP levels and degenerates mitochondria via ARL2 in neonatal rat cardiac myocytes. (2010)
  • Author(s): Nishi H, Ono K, Iwanaga Y, Horie T, Nagao K, Takemura G, Kinoshita M, Kuwabara Y, Takanabe Mori R, Hasegawa K, Kita T, Kimura T.
  • Journal Title: J Biol Chem. 285 Pages: 4920-30
  • Peer Reviewed
• [Journal Article] Neural cell adhesion molecule is a cardioprotective factor up-regulated by metabolic stress. (2010)
  • Author(s): Nagao K, Ono K, Iwanaga Y, Tamaki Y, Kojima Y, Horie T, Nishi H, Kinoshita M, Kuwabara Y, Hasegawa K, Kita T, Kimura T.
  • Journal Title: Journal of Molecular and Cellular Cardiology.
  • Peer Reviewed
• [Journal Article] Transmitral E/A ratio decreases in association with abdominal fat accumulation in patients with impaired glucose tolerance or mild diabetes without left ventricular hypertrophy. (2010)
  • Author(s): Wada H, Shinjo D, Kameda S, Ono K, Satoh N, Morimoto T, Osakada G, Nakano T, Fujita M, Shimatsu A, Hasegawa K.
  • Journal Title: Heart Vessels. 25 Pages: 45-50
  • Peer Reviewed
• [Journal Article] Soluble VEGF receptor-2 is increased in sera of subjects with metabolic syndrome in association with insulin resistance. (2010)
  • Author(s): Wada H, Satoh N, Kitaoka S, Ono K, Morimoto T, Kawamura T, Nakano T, Fujita M, Kita T, Shimatsu A, Hasegawa K.
  • Journal Title: Atherosclerosis 208 Pages: 512-517
  • Peer Reviewed
• [Journal Article] The search for Nkx2-5-regulated genes using purified embryonic stem cell-derived cardiomyocytes with Nkx2-5gene targeting. (2009)
  • Author(s): Nakashima Y, Ono K, Yoshida Y, Kojima Y, Kita T, Tanaka M, Kimura T.
  • Journal Title: Biochem Biophys Res Commun. 390 Pages: 821-826
  • Peer Reviewed
• [Journal Article] MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes. (2009)
  • Author(s): Horie T, Ono K, Nishi H, Iwanaga Y, Nagao K, Kinoshita M, Kuwabara Y, Takanabe R, Hasegawa K, Kita T, Kimura T
  • Journal Title: Biochem Biophys Res Commun. 389 Pages: 315-320
  • Peer Reviewed
• [Journal Article] Impact of CYP2C19 Polymorphisms on the Antiplatelet Effect of Clopidogrel in an Actual ClinicalSetting in Japan. (2009)
  • Author(s): Jinnai T, Horiuchi H, Makiyama T, Tazaki J, Tada T, Akao M, Ono K, Hoshino K, Naruse Y, Takahashi K, Watanabe H, Kita T, Kimura T.
  • Journal Title: Circ J. 73 Pages: 498-503
  • Peer Reviewed
• [Journal Article] MicroRNA-1 and MicroRNA-133 in Spontaneous Myocardial Differentiation of Mouse Embryonic Stem Cells. (2009)
  • Author(s): Takaya T, Ono K, Kawamura T, Takanabe R, Kaichi S, Morimoto T Wada H, Kita T, Shimatsu A, Hasegawa K.
  • Journal Title: Circ J. 73 Pages: 1492-1497
  • Peer Reviewed
• [Journal Article] Progranulin Expression in Advanced Human Atherosclerotic Plaque (2009)
  • Author(s): Kojima Y, Ono K, Inoue K, Takagi Y, Kikuta K-I, Nishimura M, Yoshida Y, Nakashima Y, Matsumae H, Furukawa Y, Mikuni N, Nobuyoshi M, Kimura T, Kita T, Tanaka M.
  • Journal Title: Atherosclerosis. 206 Pages: 102-108
  • Peer Reviewed
• [Journal Article] Progranulin Expression in Advanced Human Atherosclerotic Plaque (2009)
  • Author(s): Sugimoto M, Arai H, Tamura Y, Murayama T, Khaengkhan P, Nishio T, Ono K, Ariyasu H, Akamizu T, Ueda Y, Kita T, Harada S, Kamei K, Yokode M.
  • Journal Title: Atherosclerosis. 204 Pages: 388-394
  • Peer Reviewed
• [Presentation] MicroRNA-448 regulates adipocyte differentiation by targeting KLF5. (2010)
  • Author(s): Kinoshita M, Ono K, Kuwabara Y, Nishi H, Nagao K, Horie T, Mori R, Hasegawa K, Kita T, Kimura T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 20100305-20100307
• [Presentation] Neural cell adhesion molecule is a cardioprotective factor upregulated by metabolic stress. (2010)
  • Author(s): Nagao K, Ono K, Horie T, Kinoshita M, Nishi H, Tamaki Y, Kuwabara Y, Iwanaga Y, Kita T, Kimura T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 20100305-20100307
• [Presentation] Progranulin is expressed in the human atherosclerotic plaque and reduces IL-8 secretion from smooth muscle cells, endothelial cells, and macrophages. (2010)
  • Author(s): Kojima Y, Ono K, Inoue K, Yoshida Y, Nakashima Y, Nobuyoshi M, Kita T, Kimura T, Tanaka M.
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-07
• [Presentation] Ca2+/Calmodulin-dependent kinase kinase beta (CaMKKbeta) contributes to energy supply in adaptive phase of pressure-overload-induced heart failure. (2010)
  • Author(s): Watanabe S, Ono K, Horie T, Nagao K, Nishi H, Kinoshita M, Kuwabara Y, Kimura T.
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-07
• [Presentation] Midterm outcome of Inoue stent graft for the treatment of thoracic aortic aneurysm and dissections. (2010)
  • Author(s): Tazaki J, Tohma M, Higashitani N, Tamura T, Ono K, Marui A, Sakata R, Inoue K, Kimura T.
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-07
• [Presentation] Impact of microRNAs on cardiomyocyte metabolism. (2010)
  • Author(s): Ono K, Nishi H, Iwanaga Y, Horie T, Nagao K, Takemura G, Kinoshita M, Kuwabara Y, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-06
• [Presentation] MiR-146-mediated reduction of ErbB4 is an early event in doxorubicin-induced cardiomyocyte cell death. (2010)
  • Author(s): Horie T, Ono K, Iwanaga Y, Nishi H, Nagao K, Kinoshita M, Mori R, Kuwabara Y, Hasegawa K, Kita T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-06
• [Presentation] MicroRNA-27a regulates beta cardiac myosin heavy chaingene expression by targeting thyroid hormone receptor beta-1. (2010)
  • Author(s): Nishi H, Ono K, Horie T, Nagao K, Kinoshita M, Kuwabara Y, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T.
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-06
• [Presentation] Soluble VEGF receptor-2 is a possible novel indicator of impaired angiogenesis in metabolic syndrome. (2010)
  • Author(s): Wada H, Satoh N, Kitaoka S, Ono K, Morimoto T, Kawamura T, Nakano T, Fujita M, Kita T, Shimatsu A, Hasegawa K.
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-06
• [Presentation] Long-term clinical outcomes of unprotected left main stenting with sirolimus eluting stents : Correlation between the SYNTAX score and clinical outcomes. (2010)
  • Author(s): Shiomi H, Tamura T, Katoh Y, Tada T, Tazaki J, Jinnai T, Ono K, Kimura T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-06
• [Presentation] Implantation of sirolimus-eluting stents for coronary artery ostial stenosis in Takayasu artetitis. (2010)
  • Author(s): Shiomi H, Tamura T, Katoh Y, Tada T, Tazaki J, Jinnai T, Ono K, Kimura T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-06
• [Presentation] MicroRNA-378, which exists intronic lesion of PGC-1beta, deteriorate cardiomyocyte survival under oxidative stress. (2010)
  • Author(s): Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Watanabe S, Kinoshita M, Kojima Y, Kita T, Kimura T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-05
• [Presentation] LOX-1 is required for overexpression fo MCP-1 in mesenteric fat tissue of obese mice. (2010)
  • Author(s): Takanabe-Mori R, Ono K, Sowa N, Wada H, Takaya T, Satoh N, Shimatsu A, Fujita M, Sawamura T, Hasegawa K
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-05
• [Presentation] Roles of lectin-like oxidized low-density lipoprotein receptor-1 for glucose tolerance in normal and obese mice. (2010)
  • Author(s): Takanabe-Mori R, Ono K, Sowa N, Wada H, Takaya T, Satoh N, Shimatsu A, Fujita M, Sawamura T, Hasegawa K
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-05
• [Presentation] MicroRNA-15b, -16, 195, and -424, which have the same seed sequence, regulate ADP-rybosylation factor-like 2 and cellular ATP levels in neonatal rat cardiomyocytes (2009)
  • Author(s): Nishi H, Ono K, Horie T, Nagao K, Kinoshita M, Kuwabara-Y, Takanabe-Mori R, Hasegawa K, Takemura G, Iwanaga Y, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-17
• [Presentation] MicroRNA-378, which exists intronic lesion of PGC-1beta, deteriorate cardiomyocyte survival under oxidative stress. (2009)
  • Author(s): Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Watanabe S, Kojima Y, Kinoshita M, Mori R, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-17
• [Presentation] Aortic stenosis and acquired Type 2a von Willebrand syndrome : correlation between severity of aortic stenosis and gastrointestinal angiodysplasia (Heyde's syndrome) (2009)
  • Author(s): Sowa-N, Ono K, Horie T, Iwanaga Y, Nishi H, Nagao K, Kinoshita M, Takanabe-Mori R, Kita T, Kimura T, Hasegawa K
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-17
• [Presentation] Let-7/miR-98 family regulates the expression fo GLUT4 by targeting Mef-2C in metabolic control of cardiomyocytes. (2009)
  • Author(s): Tamura T, Tada T, Ono K, Horiuchi H, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-17
• [Presentation] Roles of lectin-like oxidized low-density lipoprotein (LDL) receptor-1 for maintenance of normal glucose tolerance in normal and obese states. (2009)
  • Author(s): Takanabe-Mori R, Ono K, Sowa N, Wada H, Takaya T, Satoh N, Shimatsu A, Fujita M, Sawamura T, Hasegawa K
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-17
• [Presentation] The identification of the NKX2-5-regulated genes using purified ES cell-derived cardiomyocytes (2009)
  • Author(s): Nakashima Y, Ono K, Yoshida Y, Kojima Y, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-16
• [Presentation] Acute doxorubicin cardiomyopathy is associated with miR-146a-induced inhibition of the neuregulin-ErbB4 pathway. (2009)
  • Author(s): Horie T, Ono K, Iwanaga Y, Nishi H, Nagao K, Kinoshita M, Kuwabara Y, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-16
• [Presentation] Neural cell adhesion molecule is a cardioprotective factor upregulated by metabolic stress. (2009)
  • Author(s): Nagao K, Ono K, Horie T, Nishi H, Kinoshita M, Kojima Y, Tamaki Y, Kuwabara Y, Iwanaga Y, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-16
• [Presentation] Inhibition of histone deacetylation markedly induces myocardial differentiation of induced pluripotent stem cells in mice. (2009)
  • Author(s): Kaichi-S, Hasegawa K, Takaya T, Morimoto T, Kawamura T, Ono K, Yokoo N, Mima T, Baba S, Doi H, Yamanaka S, Nakahata T, Heike T
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-16
• [Presentation] Expression of LOX-1 (OLR1) is markedly increased in the adipose tissue of high-fat diet-induced obese mice in close association with MCP-1. (2009)
  • Author(s): Takanabe-Mori R, Ono K, Abe Y, Wada H, Takaya T, Satoh N, Shimatsu A, Fujito M, Sawamura T, Hasegawa K
  • Organizer: American Heart Association Annual Scientific Sessions 2009
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-11-16
• [Presentation] MicroRNA-15b, -16, 195, and -424, which have the same seed sequence, regulate ADP-rybosylation factor-like 2 and cellular ATP levels in neonatal rat cardiomyocytes (2009)
  • Author(s): Nishi H, Ono K, Horie T, Nagao K, Kinoshita M, Kuwabara-Y, Takanabe-Mori R, Hasegawa K, Takemura G, Iwanaga Y, Kita T, Kimura T
  • Organizer: 第13回日本心不全学会
  • Place of Presentation: 福岡
  • Year and Date: 2009-11-01
• [Presentation] Neural cell adhesion molecule is a cardioprotective factor upregulated by metabolic stress. (2009)
  • Author(s): Nagao K, Ono K, Horie T, Nishi H, Kinoshita M, Kuwabara Y, Tamaki Y, Kojima Y, Iwanaga Y, Kita T
  • Organizer: European Society of Cardiology ongress 2009
  • Place of Presentation: Barcelona, Spein
  • Year and Date: 2009-09-01
• [Presentation] MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes (2009)
  • Author(s): Horie T, Ono K, Horie T, Nishi H, Iwanaga Y, Nagao K, Kinoshita M, Kuwabara Y, Abe Y, Takanabe R, Wada H, Hasegawa K, Kita T
  • Organizer: 第32回心筋代謝研究会
  • Place of Presentation: 大阪
  • Year and Date: 2009-07-05
• [Presentation] Let-7/miR-98 family regulates the expression of GLUT4 by targeting Mef-2C in metabolic control of cardiomyocytes. (2009)
  • Author(s): Sowa-N, Ono K, Horie T, Iwanaga Y, Nishi H, Nagao K, Kinoshita M, Takanabe-Mori R, Kita T, Kimura T, Hasegawa K
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-23
• [Book] 分子心血管病「メタボリックシンドロームと冠動脈イベントのリスク」 (2009)
  • Author(s): 尾野亘、木村剛
  • Total Pages: 9
  • Publisher: 先端医学社
• [Remarks]
  • URL: http://kyoto-u-cardio.ip/kisokenkyu/metabolic/