心筋代謝調節におけるmicroRNAの役割とその制御機構の解明

2008 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 / 糖代謝 / ATP / ミトコンドリア

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もちいてmiRNAによる心筋代謝調節遺伝子制御機構を検討する。(Dicerコンディショナルノックアウトマウス;Dicerflox/flox mice(Hannon-GJ;Cold Spring Harbor Laboratory)以後Dicer-CKO)を入手し、Creマウス(薬剤誘導性心筋特異的Cre、以後・-MHC-CreERT2マウス)と交配を開始した。Dicer-CKO;・-MHC-CreERT2マウスに8週齢でタモキシフェンを投与したところ、著明な心不全をきたした。細胞レベルでmiR-133がKLF15を介してGLUT4の発現を調節している可能性があるため、糖代謝経路について検討中である。次に、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-16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-16がミトコンドリアに存在する蛋白をターゲットとし、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-16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-16が減少し、細胞のATPが上昇した。さらにin vivoでの機能解析を続けている。

Research Products

• [Journal Article] TG-interacting factor is reauired for the differentiation of preadipocytes. (2008)
  • Author(s): Horie-T, Ono-K, Kinoshita-M, Nishi-H, Nagao-K, Kawamura-T, Abe-Y, Wada-H, Shimatsu-A, Kita-T, Hasegawa-K.
  • Journal Title: J Lipid Res. 49 Pages: 1224-34
  • Peer Reviewed
• [Journal Article] Oxidative stress induces GLUT4 translocation by activation of PI3-K/Akt and dual AMPK kinase in cardiac myocytes. (2008)
  • Author(s): Horie-T, Ono-K, Nagao-K, Nishi-H, Kinoshita-M, Kawamura-T, Wada-H, Shimatsu-A, Kita-T, Hasegawa-K.
  • Journal Title: J Cell Physiol. 215 Pages: 733-42
  • Peer Reviewed
• [Journal Article] Up-regulated expression of miicroRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet. (2008)
  • Author(s): Takanabe R, Ono K, Abe Y, Takaya T, Horie T, Wada H, Kita T, Satoh N, Shimatsu A, Hasegawa K.
  • Journal Title: Biochem Biophys Res Commun. 376 Pages: 728-32
  • Peer Reviewed
• [Journal Article] Inhibition of CCN1 suppressed neointimal hyperplasia in a rat balloon injury model. (2008)
  • Author(s): Matsumae-H, Yoshida-Y, Ono-K, Togi-K, Inoue-K, Furukawa-Y, Nakashima-Y, Koima-Y, Nobuyoshi-M, Kita-T, Tanak-M.
  • Journal Title: Arterioscler Thromb Vase Biol. 28 Pages: 1077-83
  • Peer Reviewed
• [Journal Article] Small dense LDL-cholesterol relative to LDL-cholesterol is a strong independent determinant of hypoadiponectinemia in metabolic syndrome. (2008)
  • Author(s): Satoh-N, Wada-H, Ono-K, Yamakage-H, Yamada-K, Nakano-T, Hattori-M, Shimatsu-A, Kuzuya-H, Hasegawa-K.
  • Journal Title: Circulation J 72 Pages: 932-9
  • Peer Reviewed
• [Journal Article] Statins activate GATA-6 and induce differentiated vascular smooth muscle cells. (2008)
  • Author(s): Waa H, Abe M, Ono K, Morimoto T, Kawamura T, Takaya T, Satoh N, Fujita M, Kita T, Shimatsu A, Hasegawa K.
  • Journal Title: Circulation J 374 Pages: 731-6
  • Peer Reviewed
• [Journal Article] Morphological and biochemical characterization of basal and starvation-induced autophagy in isolated adult rat cardiomyocytes. (2008)
  • Author(s): Maruyama R, Goto K, Takemra G, Ono K, Nagao K, Horie T, Tsujimoto A, Kanamori H, Miyata S, Ushikoshi H, Nagashima K, Minatoguchi S, Fuj iwara T, Fuj iwara H.
  • Journal Title: Am J Physiol Heart Circ Physiol. 295 Pages: H1599-607
  • Peer Reviewed
• [Journal Article] Identification of p300-targeted acetylated residues in GATA-4 during hypertrophic responses in cardiac myocytes. (2008)
  • Author(s): Takaya T, Kawaiura T, Moriffloto T, Ono K, Kita T, Shimatsu A, Hasegawa K.
  • Journal Title: J Biol Chem. 283 Pages: 9828-35
  • Peer Reviewed
• [Journal Article] Mulberry leaf ameliorates the expression profile of adipocytokines by inhibiting oxidative stress in white adipose tissue in db/db mice. (2008)
  • Author(s): Sugimoto M, Arai H, Taraura 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. (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Inhibition of CCR2 Ameliorates Insulin Resistance and Hepatic Steatosis in db/db Mice. (2008)
  • Author(s): Taiura Y, Sugimoto M, Murayama T, Ueda Y, Kanamori H, Ono K, Ariyasu H, Akamizu T, Kita T, Yokode M, Arai H.
  • Journal Title: Arterioscler Thromb Vase Biol. 28 Pages: 2195-201
  • Peer Reviewed
• [Presentation] Neural cell adhesion molecule is upregulated by metabolic stress and enhances the cardiomyocyte survival rate through neurite-cardiomyocyte communication (2008)
  • Author(s): Nagao K, Ono K, Horie T, Koj ima Y, Nishi H, Kinoshita M, Kita T
  • Organizer: American Heart Association Annual Scientific Sessions
  • Place of Presentation: New Orleans, Louisiana
  • Year and Date: 20081108-20081112
• [Presentation] NF-kB-dependent induction of microRNA-146 downregulates ErbB4 and may be involved in the deterioration of cardiomyocyte survival (2008)
  • Author(s): Horie T, Ono K, Iwanaga Y, NishiH, Nagao K, Kinoshita M, Mori R, Hasegawa K, Kita T
  • Organizer: American Heart Association Ammual Scientific Sessions
  • Place of Presentation: New Orleans, Louisiana
  • Year and Date: 20081108-20081112
• [Presentation] Upregulation of microRNA-27a, which downregulates retionoid X receptor a, controls cardiac myosin heavy chain gene expression in neonatal rat cardioyocyte (2008)
  • Author(s): Nishi H, Ono K, Kinoshita M, Nagao K, Horie T, Takanabe R, Hasegawa K, Iwanaga Y, Kita T
  • Organizer: American Heart Association Annual Scientific Sessions
  • Place of Presentation: New Orleans, Louisiana
  • Year and Date: 20081108-20081112
• [Presentation] Up-regulatex expression of microaRNA-143 in association with obesity in the adipose tissue of mice fed with high fat diet (2008)
  • Author(s): Takanabe R, Ono K, Takaya T, Horie T, Wada H, Kita T, Shimatsu A, Hasegawa K
  • Organizer: American Heart Association Annual Scientific Sessions
  • Place of Presentation: New Orleans, Louisiana
  • Year and Date: 20081108-20081112
• [Presentation] IGF axis and adiponectin as prognostic markers of patients with congestive heart failure (2008)
  • Author(s): Watanabe S, Tamura T, Ono K, Kita T, Kimura T, Furukawa Y
  • Organizer: European Society of Cardiology Congres
  • Place of Presentation: Munich, Germany
  • Year and Date: 20080830-20080903
• [Presentation] miR-133は心筋細胞における代謝調節においてKLF15をターゲットとしてGLUT4の発現を制御している. (2008)
  • Author(s): 堀江貴裕, 尾野亘, 西仁勇, 長央和也, 木下美菜子, 森利依子, 岩永善高, 長谷川浩二, 北徹
  • Organizer: 第45回日本臨床分子医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20080724-20080725
• [Presentation] miR-27aはラット心筋細胞においてミオシン重鎖の発現を制御する (2008)
  • Author(s): 西仁勇, 尾野亘, 木下美菜子, 長央和也, 堀江貴裕, 岩永善高, 森利依子, 長谷川浩二, 北徹
  • Organizer: 第45回本臨床分子医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20080724-20080725
• [Presentation] microRNA-1の過剰発現はマウスES細胞の心筋分化を抑制する (2008)
  • Author(s): 高谷智英, 川村晃久, 尾野亘, 高鍋利依子, 鶏内伸二, 馬場志郎, 平家俊男, 中畑龍俊, 森本達也, 北徹, 島津章, 長谷川浩二
  • Organizer: 第45回日本臨床分子医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20080724-20080725
• [Presentation] Trapping genes that encode secreted and transmembrane proteins in H9C2 cardiomyoblasts. (2008)
  • Author(s): Nagao K, Ono K, Horie T, Nishi H, Kinoshita M, Hasegawa K, Kita T
  • Organizer: 第31回心筋代謝研究会
  • Place of Presentation: 東京
  • Year and Date: 20080712-20080713
• [Presentation] Upregulation of microRNA targeting retionoid X receptor a contributes to development of cardiachypertrophy (2008)
  • Author(s): Nishi H, Ono K, Horie T. Kinoshita M. Nagao K, Iwanaga Y, Hasegawa K, Kita T
  • Organizer: 第72回日本循環器学会
  • Place of Presentation: 福岡
  • Year and Date: 20080328-20080330
• [Presentation] MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control incardiac myocytes (2008)
  • Author(s): Horie T, Ono K, Kinoshita M, Nishi H, Nagao K, Mori R, Iwanaga Y, Hasegawa K, Kita T
  • Organizer: 第72回日本循環器学会
  • Place of Presentation: 福岡
  • Year and Date: 20080328-20080330
• [Presentation] Overexpression of microRNA-1 in mouse embryonic stem cells represses myocardial differentiation (2008)
  • Author(s): Takaya-T, Kawamura T, Ono K, Takanabe R, Kaichi S, Kita T, Wada H, Morimoto T, Shimatsu A, Hasegawa K
  • Organizer: 第72回日本循環器学会
  • Place of Presentation: 福岡
  • Year and Date: 20080328-20080330
• [Presentation] A soluble VEGF receptor-2 is possible novel biomarker of cardiovascular risk in the metabolic syndrome. (2008)
  • Author(s): Wada H, Satoh N, Ono K, Shinjo D, Morimoto T, Nakano T, Shimatsu A, Fujita M, Hasegawa K
  • Organizer: 第72回日本循環器学会
  • Place of Presentation: 福岡
  • Year and Date: 20080328-20080330
• [Presentation] Cyclin-dependent kinase-9 is required for the differentiation of mouse ES cells into cardiac myocytes. (2008)
  • Author(s): Kaichi S, Takaya T, Sunagawa Y, Kawamura T, Ono K, Moriraoto T, Kita T, Baba S, Hidaka K, Morisaki T, Heike T, Nakahata T, Shimatsu A, Hasegawa K
  • Organizer: 第72回日本循環器学会
  • Place of Presentation: 福岡
  • Year and Date: 20080328-20080330
• [Presentation] microRNAをターゲットとした肥満に伴う心血管系疾患治療法の開発 (2008)
  • Author(s): 尾野亘, 堀江貴裕, 西仁勇, 長央和也, 木下美菜子, 北徹
  • Organizer: 第4回メタボリックシンドローム研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-01-19