マイクロＲＮＡ－３３ａ／ｂとそのパッセンジャー鎖による代謝調節機構の解明

• Project/Area Number: 14J05148
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: 西野 共達 京都大学, 医学研究科, 特別研究員(PD)
• Project Period (FY): 2014-04-25 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2014: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: マイクロRNA / 脂質代謝 / コレステロール / 動脈硬化 / 核酸医療 / HDL-コレステロール

Outline of Annual Research Achievements

1) miR-33bと動脈硬化: miR-33b+/+Apoe-/-マウスでは、miR-33b-/-Apoe-/-マウスと比べて、血清HDL-C値の低下を認め、動脈硬化巣の増大と質的悪化を認めた。またこれまでmiR-33a欠損マウスでは認められなかったリポ蛋白代謝の変化を認めた。
2) miR-33欠損マウスとmiR-33bノックインマウスの交配: miR-33a-/-miR-33b-/-マウス(miR-33欠損マウス)、miR-33a+/+miR-33b-/-マウス(野生型)、miR-33a-/-miR-33b+/+マウス(ノックインノックアウトマウス)、miR-33a+/+miR-33b+/+マウス(miR-33bノックインマウス、ヒト化マウス)の四系統のマウスの樹立し、血清脂質プロファイル等のデータを収集した。結果、臓器・組織特異的にmiR-33a, miR-33bの発現レベルに違いがあることが明らかとなった。一例として、肝臓においてはmiR-33bがmiR-33aよりも多く発現し、血清HDL-C値に与える影響がより大きいことが明らかとなった。これらは今後の臓器・組織特異的なmiR-33a/b抑制治療を見据えた上での重要なデータとなる。
3) 臓器特異的miR-33a欠損マウスを用いた検討: miR-33aflox/floxマウスを樹立し、肝臓特異的miR-33a欠損マウスを確立した。全身ノックアウトマウスと同様に血清HDL-C値が上昇することが確認した。今後全身ノックアウトマウスで確認された表現型との関連について研究を進める。また、線維芽細胞特異的miR-33aノックアウト(Periostin-Cre)を用い、心臓線維芽細胞におけるコレステロール代謝が、心不全モデルにおける線維化に関わることが明らかとした(Nishiga M et al, Circ Res 2016)。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model. (2017)
  • Author(s): Izuhara M, Kuwabara Y, Saito N, Yamamoto E, Hakuno D, Nakashima Y, Horie T, Baba O, Nishiga M, Nakao T, Nishino T, Nakazeki F, Ide Y, Kimura M, Kimura T, Ono K.
  • Journal Title: PLoS One Volume: 12(3) Issue: 3 Pages: e0172798-e0172798
  • DOI: 10.1371/journal.pone.0172798
  • Peer Reviewed / Open Access
• [Journal Article] Dynamic changes of serum microRNA-122-5p through therapeutic courses indicates amelioration of acute liver injury accompanied by acute cardiac decompensation. (2017)
  • Author(s): Satoshi Koyama, Takashi Kuragaichi, Yukihito Sato, Yasuhide Kuwabara, Shunsuke Usami, Takahiro Horie, Osamu Baba, Daihiko Hakuno, Yasuhiro Nakashima, Tomohiro Nishino, Masataka Nishiga, Tetsushi Nakao, Hidenori Arai, Takeshi Kimura, Koh Ono
  • Journal Title: ESC Heart Failure Volume: 4 Issue: 2 Pages: 112-121
  • DOI: 10.1002/ehf2.12123
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. (2016)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Hakuno D, Nakashima Y, Nishi H, Nakazeki F, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Inada T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K.
  • Journal Title: Circ Res. Volume: - Issue: 5 Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after percutaneous coronary intervention: a report from the CREDO-Kyoto registry cohort-2. (2015)
  • Author(s): Izuhara M, Ono K, Shiomi H, Morimoto T, Furukawa Y, Nakagawa Y, Shizuta S, Tada T, Tazaki J, Horie T, Kuwabara Y, Baba O, Nishino T, Kita T, Kimura T; CREDO-Kyoto PCI/CABG Registry Cohort-2 Investigators.
  • Journal Title: Atherosclerosis. Volume: 242(2) Issue: 2 Pages: 632-8
  • DOI: 10.1016/j.atherosclerosis.2015.05.010
  • NAID: 120005678183
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNAs and High-Density Lipoprotein Cholesterol Metabolism (2015)
  • Author(s): Ono K, Horie T, Nishino T, Baba O, Kuwabara Y, Kimura T.
  • Journal Title: International Heart Journal Volume: 56 Issue: 4 Pages: 365-371
  • DOI: 10.1536/ihj.15-019
  • NAID: 130005087574
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Expression Patterns of miRNA-423-5p in the Serum and Pericardial Fluid in Patients Undergoing Cardiac Surgery. (2015)
  • Author(s): Miyamoto S, Usami S, Kuwabara Y, Horie T, Baba O, Hakuno D, Nakashima Y, Nishiga M, Izuhara M, Nakao T, Nishino T, Ide Y, Nakazeki F, Wang J, Ueyama K, Kimura T, Ono K.
  • Journal Title: PLoS One. Volume: 10(11) Issue: 11 Pages: e0142904-e0142904
  • DOI: 10.1371/journal.pone.0142904
  • NAID: 120005749912
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33a/b in Lipid Metabolism (2015)
  • Author(s): Ono K, Horie T, Nishino T, Baba O, Kuwabara Y, Yokode M, Kita T, Kimura T.
  • Journal Title: Circulation Journal Volume: 79 Issue: 2 Pages: 278-284
  • DOI: 10.1253/circj.CJ-14-1252
  • NAID: 130004927073
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. (2015)
  • Author(s): Kuwabara Y, Horie T, Baba O, Watanabe S, Nishiga M, Usami S, Izuhara M, Nakao T, Nishino T, Otsu K, Kita T, Kimura T, Ono K.
  • Journal Title: Circulation Research Volume: 116 Issue: 2 Pages: 279-288
  • DOI: 10.1161/circresaha.116.304707
  • Peer Reviewed
• [Journal Article] Interpapillary muscle distance independently affects severity of functional mitral regurgitation in patients with systolic left ventricular dysfunction. (2014)
  • Author(s): Kim K, Kaji S, An Y, Nishino T, Tani T, Kitai T, Furukawa Y.
  • Journal Title: The Journal of Thoracic and Cardiovascular Surgery Volume: 148 Issue: 2 Pages: 434-440
  • DOI: 10.1016/j.jtcvs.2013.09.029
  • Peer Reviewed
• [Journal Article] MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo. (2014)
  • Author(s): Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Nakazeki F, Ide Y, Koyama S, Sowa N, Yahagi N, Shimano H, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 5312-5312
  • DOI: 10.1038/srep05312
  • Peer Reviewed / Open Access
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice (2017)
  • Author(s): Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kimura T and Ono K
  • Organizer: Keystone Symposium RNA-Based Approaches in Cardiovascular Diseases
  • Place of Presentation: Keystone, CO, USA
  • Int'l Joint Research
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice (2017)
  • Author(s): Nishino T, Horie T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kimura T and Ono K
  • Organizer: 第81回日本循環器学会総会学術集会
  • Place of Presentation: 金沢、日本
  • Int'l Joint Research
• [Presentation] MicroRNA-33bは動脈硬化形成を促進させる (2016)
  • Author(s): 西野共達、堀江貴裕、馬場理、桑原康秀、中尾哲史、西賀雅隆、宇佐美俊輔、出原正康、中関典子、井手裕也、小山智史、木村剛、尾野亘
  • Organizer: 第48回日本動脈硬化学会総会
  • Place of Presentation: 東京、日本
  • Year and Date: 2016-07-14
• [Presentation] MicroRNA-33b promotes formation of vulnerable atherosclerotic plaque (2016)
  • Author(s): Tomohiro Nishino
  • Organizer: 新学術領域 転写体者システム若手ワークショップ
  • Place of Presentation: 山梨県
  • Year and Date: 2016-02-04
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in vivo (2015)
  • Author(s): Tomohiro Nishino, Takahiro Horie, Osamu Baba, Yasuhide Kuwabara, Koh Ono
  • Organizer: 新学術領域 転写代謝システム若手ワークショップ
  • Place of Presentation: 群馬
  • Year and Date: 2015-02-06
• [Presentation] MicroRNA-33, located within Srebf2 intron, regulate fatty acid synthesis via targeting SREBF-1 in vivo (2014)
  • Author(s): Tomohiro Nishino, Takahiro Horie, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Fumiko Nakazeki, Yuya Ide, Satoshi Koyama, Naoya Sowa Takeshi Kimura, Koh Ono
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-27
• [Presentation] Microrna-33, Located within Srebf2 Intron, Regulate Fatty Acid Synthesis Via Targeting SREBP-1 in vivo (2014)
  • Author(s): T. Nishino, T. Horie, O. Baba, Y. Kuwabara, T Nakao, M. Nishiga, S. Usami, M. Izuhara, Y. Ide, F. Nakazeki, S. Koyama, M. Yokode, T. Kita, T. Kimura, K. Ono
  • Organizer: AHA Scientific Sessions 2014
  • Place of Presentation: 米国 シカゴ
  • Year and Date: 2014-11-17
• [Presentation] microRNA-33, embedded in Srebf2 intron, regulate fatty acid synthesis through targeting SREBP-1 in vivo (2014)
  • Author(s): T. Nishino, T. Horie, O. Baba, Y. Kuwabara, T. Nakao, M. Nishiga, S. Usami, M. Izuhara, K. Ono
  • Organizer: MSDA 2014: 9th Metabolic Syndrome, Type2 Diabetes and Atherosclerosis Congress
  • Place of Presentation: 京都
  • Year and Date: 2014-09-13
• [Presentation] MicroRNA-33a, embedded in Srebf2 gene, regulate lipogenetic pathway in vivo (2014)
  • Author(s): T. Nishino, T. Horie, O. Baba, Y. Kuwabara, T. Nakao, M. Nishiga, S. Usami, M. Izuhara, K. Ono
  • Organizer: ESC CONGRESS 2014
  • Place of Presentation: スペイン バルセロナ
  • Year and Date: 2014-09-01
  • Invited
• [Presentation] microRNA-33は生体内でSREBP-1を介して脂肪酸合成を制御する (2014)
  • Author(s): 西野共達
  • Organizer: 新学術領域 転写代謝システム班会議
  • Place of Presentation: 仙台
  • Year and Date: 2014-07-12
• [Remarks] 京都大学医学部附属病院 循環器内科
  • URL: http://kyoto-u-cardio.jp/
• [Remarks] 京都大学医学部附属病院循環器内科 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/