心筋代謝調節におけるmicroRNAの役割とその制御機構の解明

2010 Fiscal Year Annual Research Report

• Project/Area Number: 20590864
• Research Institution: Kyoto University
• Principal Investigator: 尾野 亘 京都大学, 医学研究科, 講師 (00359275)
• Keywords: microRNA / 動脈硬化 / コレステロール / SREBP2 / ABCA1

Research Abstract

糖代謝・脂質代謝に関わるmicroRNA(miRNA)を探る中で、これらの制御に関わる遺伝子のイントロンにあるmiRNAについても検討を開始した。
細胞内コレステロールレベルを厳密にコントロールすることは細胞の生存にとって大変重要である。
Sterol regulatory element-binding protein 2 (SREBP-2)は細胞内のコレステロールの低下を感知して、細胞がコレステロール不足から守る働きがある。すなわち、コレステロール合成や取り込みに関わる遺伝子を正に制御し、また末梢の細胞においてはコレステロールの引き抜きに関わるATP-binding cassette transporter A1 (ABCA1)を負に制御する。我々はSrebp2のイントロンに存在するmiR-33欠損マウスを作成し、miR-33がSREBP-2のABCA1に対する機能を増強していること、また血中HDLの低下に関わることを示した。さらにこのマウスが動脈硬化に抵抗性かどうかを検討するために、ApoE欠損マウスとの交配も行い、組織学的検討を行っている。さらに心臓での代謝調節への影響についても検討中である。
新たな治療標的miRNAの解明の研究計画においては、肥満および糖尿病モデル動物でのmiRNA発現プロファイル解析で得られたmiRNAについて、miR-デコイ遺伝子を用いた抑制系をもとに、詳細な機能解析を行っている。すでに特異的反応を示したmiRNAについてはfloxマウスを海外から導入ずみで、心筋特異的Creマウスと掛け合わせ、生体内での影響を検討する予定である。
また、心血管疾患患者の血液サンプルにおいて血中の循環miRNAの測定を行った。血清miR-133の上昇が心筋障害のマーカーのトロポニンTと相関し、トロポニンTが上昇するより以前に上昇する鋭敏な指標であることを認めた。

Research Products

• [Journal Article] MicroRNA-33 encoded by an intron of Srebp2 regulates HDL in vivo (2010)
  • Author(s): Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, Kinoshita M, Kuwabara Y, Marusawa H, Iwanaga Y, Hasegawa K, Yokode M, Kimura T, Kita T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 107 Pages: 17321-6
  • Peer Reviewed
• [Journal Article] Regulation of adipocyte differentiation by activation of serotonin (5-HT) receptors 5-HT2AR and 5-HT2CR and involvement of microRNA-448-mediated repression of KLF5. (2010)
  • Author(s): Kinoshita M, Ono K, Horie T, Nagao K, Nishi H, Kuwabara Y, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T.
  • Journal Title: Molecular Endoclinology. Volume: 24 Pages: 1978-87
  • Peer Reviewed
• [Journal Article] Acute Doxorubicin Cardiotoxicity Is Associated with miR-146a-induced Inhibition of the Neuregulin-ErbB Pathway (2010)
  • Author(s): Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe-Mori R, Nishi E, Hasegawa K, Kita T, Kimura T.
  • Journal Title: Cardiovascular Res Volume: 87 Pages: 656-664
  • Peer Reviewed
• [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. Volume: 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. Volume: 48 Pages: 1157-68
  • Peer Reviewed
• [Journal Article] Metaxin deficiency alters mitochondrial membrane permeability and leads to resistance to TNF-induced cell killing. (2010)
  • Author(s): Ono K, Wang X, Kim SO, Armstrong LC, Bornstein P, Han J.
  • Journal Title: Protein Cell Pages: 161-173
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure : association with adiponectin. (2010)
  • Author(s): Watanabe S, Tamura T, Ono K, Horiuchi H, Kimura T, Kita T, Furukawa Y.
  • Journal Title: Eur J Heart Failure Volume: 12 Pages: 1214-22
  • Peer Reviewed
• [Journal Article] LOX-1 is required for the adipose tissue expression of proinflammatory cytokines in high-fat diet-induced obese mice. (2010)
  • Author(s): Takanabe-Mori R, Ono K, Sowa N, Takaya T, Horie T, Satoh-Asahara N, Shimatsu A, Fujita M, Sawamura T, Hasegawa K.
  • Journal Title: Biochem Biophys Res Commun Volume: 398 Pages: 576-80
  • Peer Reviewed
• [Journal Article] Cell line-dependent differentiation of induced pluripotent stem cells into cardiomyocytes in mice. (2010)
  • Author(s): Kaichi S, Hasegawa K, Takaya T, Yokoo N, Mima T, Kawamura T, Morimoto T, Ono K, Baba S, Doi H, Yamanaka S, Nakahata T, Heike T.
  • Journal Title: Cardiovasc Res. Volume: 88 Pages: 314-3
  • 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. Volume: 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 Volume: 208 Pages: 512-517
  • Peer Reviewed
• [Journal Article] A case with sudden onset of position-dependent hypoxemia caused by reopening of foramen ovale. (2010)
  • Author(s): Tada T, Fujita M, Goto T, Tamura T, Ono K, Kita T, Takahashi K, Nagata H, Sakata R, Kimura T
  • Journal Title: Journal of Cardiology Cases Volume: 1 Pages: e88-e91
  • Peer Reviewed
• [Presentation] MicroRNA 26b family encoded by the introns of small CTD Phosphatases (SCPs) 1 to 3 suppresses phenylephrine-induced cardiomyocyte hypertrophy by targeting TRPC3/6 and GATA4 (2010)
  • Author(s): Ono K, Sowa N, Horie T, Hasegawa K, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] MiR-146a-induced inhibition of the neuregulin-ErbB4 pathway may be involved in deterioration of cardiotoxicity under concurrent chemotherapy with doxorubicin and Trastuzumab. (2010)
  • Author(s): Horie T, Ono K, Iwanaga Y, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe-Mori R, Nishi E, Hasegawa K, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] Ca2+/Calumodulin-dependent kinase kinase beta contributes to energy supply in adaptive phase of pressure-overload-induced heart failure. (2010)
  • Author(s): Watanabe S, Ono K, Horie T, Nishi H, Kinoshita M, Kuwabara Y, Baba O, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] MicroRNA-27a regulates beta-myocin heavy chain gene expression by targeting thyroid hormone receptor beta 1 in neonatal rat ventricular myocytes. (2010)
  • Author(s): Nishi H, Ono K, Horie T, Nagao K, Kinoshita M, Kuwabara Y, Baba O, Nakashima Y, Nagao K, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] MicroRNA-1 and microRNA-133a are useful as early diagnostic biomarkers in patients with acute coronary syndrome. (2010)
  • Author(s): Kuwabara Y, Ono K, Horie T, Nishi H, Kinoshita M, Watanabe S, Nakashima Y, Nagao K, Kojima Y, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] Serum adiponectin levels are increased by pathophysiologically induced left ventricular hypertrophy. (2010)
  • Author(s): Wada H, Akao M, Masunaga N, Takaya T, Takanabe-Mori R, Abe M, Funatsu J, Nakajima Y, Kanasaki M, Osakabe G, Nakano T, Ono K, Satoh-Asahara N, Shimatsu A, Hasegawa K
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] Lox-1 is required for the adiposal expression of proinflammatory cytokines in high-fat diet-induced obese mice. (2010)
  • Author(s): Takanabe-Mori R, Ono K, Sowa N, Wada H, Takaya T, Satoh-Asahara N, Shimatsu A, Fujita M, Sawamura T, Hasegawa K
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] Metastasis-associated protein S100A4 contributes to cardiac fibrosis through the modulation of PTEN. (2010)
  • Author(s): Tamaki Y, Okuda J, Niizuma S, Kawashima T, Kato T, Inuzuka Y, Shioi T, Ono K, Koshimizu T, Miyazaki S, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 20101113-20101117
• [Presentation] Ca2+/calmodulin-dependent kinase kinase beta contributes to energy supply in adaptive phase of pressure-overload-induced heart failure. (2010)
  • Author(s): Watanabe S, Ono K, Horie T, Nishi H, Kuwabara Y, Kimura T
  • Organizer: European Society of Cardiology Congress 2010
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 20100828-20100901
• [Presentation] Ca2+/calmodulin-dependent kinase kinase β(CaMKKβ)contributes to energy supply in adaptive phase of pressure-overload-induced heart failure (2010)
  • Author(s): Watanabe S, Ono K, Kimura T
  • Organizer: 第33回心筋代謝研究会
  • Place of Presentation: 東京
  • Year and Date: 20100703-20100704
• [Presentation] MicroRNA-15b modulates cellular ATP levels and degenerates mitochondria via Ar12 in neonatal rat cardiac myocytes. (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: ISHR World Congress 2010 Kyoto
  • Place of Presentation: Kyoto
  • Year and Date: 20100513-20100516
• [Presentation] ドキソルビシンによる心筋障害にはmiR-146aによるneuregulin/ErbBシグナルの抑制が関わる (2010)
  • Author(s): 堀江貴裕、尾野亘、西仁勇、長央和也、木下美菜子、桑原康秀、森利依子、長谷川浩二、北徹、木村剛
  • Organizer: 第47回日本臨床分子医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20100410-20100411
• [Presentation] MicroRNA-448は脂肪細胞分化を抑制する (2010)
  • Author(s): 木下美菜子、尾野亘、桑原康秀、西仁勇、長央和也、堀江貴裕、森利依子、長谷川浩二、北徹、木村剛
  • Organizer: 第47回日本臨床分子医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20100410-20100411
• [Presentation] SREBP2のイントロンにコードされるマイクロRNA-33は生体においてHDLの形成を制御する (2010)
  • Author(s): 堀江貴裕、尾野亘、西仁勇、長央和也、木下美菜子、桑原康秀、森利依子、長谷川浩二、北徹、木村剛
  • Organizer: 第2回 京阪神心不全研究会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-04
• [Book] Biology topics.MicroRNAと心疾患 (2010)
  • Author(s): 尾野亘、木村剛
  • Total Pages: 4
  • Publisher: Bio Clinica
• [Book] 「心筋梗塞モデル(小動物)」循環器疾患-疾患モデルの作成と利用 (2010)
  • Author(s): 尾野亘
  • Total Pages: 5
  • Publisher: Life Science Information center
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/