2014 Fiscal Year Annual Research Report
| Project/Area Number |
25670383
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| Research Institution | Kyoto University |
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Principal Investigator |
尾野 亘 京都大学, 医学(系)研究科(研究院), 准教授 (00359275)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Keywords | ステント / 冠動脈 / 血管内皮細胞 |
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| Outline of Annual Research Achievements |
近年、冠動脈疾患治療には血管平滑筋細胞の増殖抑制作用を持つ薬剤溶出性ステントが用いられている。しかし、これは同時に血管内皮細胞の増殖も抑制するため、血栓症や慢性炎症を引き起こすことが問題となっている。すなわち、理想的な血管治療においては、①治療部位の血管内皮細胞を再生させ、かつ②再狭窄の主体となる平滑筋細胞の増殖を抑制することである。
我々は、これまでに血管内皮細胞を誘導し、抗炎症作用を持つマイクロRNA(miR)-126に着目し研究を行っている。その過程で、このmiR-126が直接血管平滑筋の増殖抑制も起こすことを見出し、上記の①②を同時に満たす最適なマイクロRNAであると判断した。まず、このmiR-126をPLGA（乳酸・グリコール酸共重合体）ナノ粒子に封入し、ステントに電着し、miR126徐放化ステントを作成した。
次に、このステントの効果をウサギの腸骨動脈を用いて検証した。miR-126搭載ステントにおいて、コントロールRNAと比較して、有意に再狭窄予防効果を認めた。実際に局所での血管内皮細胞の再生および、平滑筋細胞の増殖抑制を認めた。この結果により日｢マイクロＲＮＡ溶出型ステント及びそれを用いた管腔治療｣ として特許を出願した（特願2014-044463）。さらにブタ冠動脈モデルでの実験も施行し、現在結果の解析中である。
このシステムにより、複数のマイクロRNAや生理活性物質の徐放化も可能であるため、幅広い研究展開も可能となると考えられる。
冠動脈ステントは現在でも外国の製品が主流である。本研究により、それらを上回る機能（抗血栓性、抗炎症性）を持つ日本発の製品を作り出すことが可能となる。すでに医薬品医療機器総合機構において戦略相談事前面談を行った。フォローアップ面談を受け、さらに臨床研究のプロトコールを確定する予定である。
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[Journal Article] MicroRNA-451 Exacerbates Lipotoxicity in Cardiomyocytes and High-Fat Diet-Induced Cardiac Hypertrophy in Mice through Suppression of the LKB1/AMPK Pathway2015
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.
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Journal Title
Circ Res.
Volume: 116
Pages: 279-88
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Cardiac-specific inhibition of kinase activity in calcium/calmodulin-dependent protein kinase kinase- leads to accelerated left ventricular remodeling and heart failure after transverse aortic constriction in mice.2014
Author(s)
Watanabe S, Horie T, Nagao K, Kuwabara Y, Baba O, Nishi H, Sowa N, Narazaki M, Matsuda T, Takemura G, Wada H, Hasegawa K, Kimura T, and Ono K.
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Journal Title
PLoS One
Volume: 9
Pages: e108201
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Effect of Preinfarction Angina Pectoris on Long-term Survival in Patients With ST-Segment Elevation Myocardial Infarction Who Underwent Primary Percutaneous Coronary Intervention.2014
Author(s)
Taniguchi T, Shiomi H, Toyota T, Morimoto T, Akao M, Nakatsuma K, Ono K, Makiyama T, Shizuta S, Furukawa Y, Nakagawa Y, Ando K, Kadota K, Horie M, Kimura T.
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Journal Title
Am J Cardiol.
Volume: 114
Pages: 1179-86
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Incidence and Outcome of Surgical Procedures After Coronary Artery Bypass Grafting Compared With Those After Percutaneous Coronary Intervention: A Report From the Coronar Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG Registry Cohort-2.2014
Author(s)
Tokushige A, Shiomi H, Morimoto T, Ono K, Furukawa Y, Nakagawa Y, Kadota K, Ando K, Shizuta S, Tada T, Tazaki J, Kato Y, Hayano M, Abe M, Hamasaki S, Ohishi M, Nakashima H, Mitsudo K, Nobuyoshi M, Kita T, Imoto Y, Sakata R, Okabayashi H, Hanyu M, Shimamoto M, Nishiwaki N, Komiya T, Kimura T
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Journal Title
Circ Cardiovasc Interv.
Volume: 7
Pages: 482-91.
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Anticoagulant and antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention.2014
Author(s)
Goto K, Natsaki M, Yahata M, Ono K, Kadota K, Takatsu Y, Tamura T,Takizawa A, Inada T, Doi O, Nohara R, Matsuda M, Takeda T, Kato M, Shirotani M, Eizawa H, Ishii K, Lee JD, Takahashi M, Horie M, Takahashi M, Miki S, Aoyama T, Suwa S, Hamasaki S, Ogawa H, Mitsudo K, Nobuyoshi M, Kita T, Kim ra T
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Journal Title
Am J Cardiol.
Volume: 114
Pages: 70-8.
DOI
Peer Reviewed / Acknowledgement Compliant
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[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.
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Journal Title
Sci Rep.
Volume: 4
Pages: 5312
DOI
Peer Reviewed / Open Access
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[Journal Article] Long-Term Efficacy and SafetyOutcomes After Unrestricted Use of Drug-Eluting Stents in Patients With AcuteCoronary Syndrome.2014
Author(s)
Kawaji T, Shiomi H, Morimoto T, Tamura T, Nishikawa R, Yano M, Tazaki J, Imai M, Saito N, Makiyama T, Shizuta S, Ono K, Kimura T.
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Journal Title
Circ J.
Volume: 78
Pages: 1628-35
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Evolution in practice patterns and long-term outcomes of coronary revascularization from bare-metal stent era to drug-eluting stent era in Japan.2014
Author(s)
Shiomi H, Morimoto T, Makiyama T, Ono K, Furukawa Y, Nakagawa Y, Kadota K, Onodera T, Takatsu Y, Mitsudo K, Kita T, Sakata R, Okabayashi H, Hanyu M, Komiya T, Yamazaki F, Nishiwaki N, Kimura T; CREDO-Kyoto Investigators.
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Journal Title
Am J Cardiol.
Volume: 113
Pages: 1652-9
DOI
Peer Reviewed / Acknowledgement Compliant
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[Presentation] Microrna-33, Located Within Srebf2 Intron, Regulate Fatty Acid Synthesis via Targeting SREBP-1 in vivo2014
Author(s)
1)Nishino T, Horie T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Ide Y, Nakazeki F, Koyama S, Yokode M, Kita T, Kimura T, Ono K.
Organizer
American Heart Association Annual Scientific Sessions 2014
Place of Presentation
Chicago
Year and Date
2014-11-15 – 2014-11-19
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[Presentation] MicroRNA-33b Knock-in Mice for an Intron of Sterol Regulatory Element-Binding Factor 1 (Srebf1) Exhibit Reduced HDL-C in vivo2014
Author(s)
2)Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Ide Y, Nakazeki F, Koyama S, Yokode M, Kita T, Kimura T, Ono K.
Organizer
American Heart Association Annual Scientific Sessions 2014
Place of Presentation
Chicago
Year and Date
2014-11-15 – 2014-11-19
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[Presentation] Serum HDL-C decreases in microRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1).2014
Author(s)
Horie T, Nishino T, Baba O, Kuwabara Y, Nakano T, Nishiga M, Usami S, Izuhara M, Kimura T, Ono K.
Organizer
9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
Place of Presentation
Kyoto
Year and Date
2014-09-12 – 2014-09-14
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[Presentation] MicroRNA-33 deficiency reduces atherosclerotic plaque progression in apoE knockout mice.2014
Author(s)
Baba O, Horie T, Ono K, Kuwabara Y, Sowa N, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T.
Organizer
9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
Place of Presentation
Kyoto
Year and Date
2014-09-12 – 2014-09-14
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[Presentation] MicroRNA-451 is involved in diabetic cardiomyopathy through suppression of the LKB1/AMPK pathway.2014
Author(s)
Kuwabara Y, Horie T, Baba O, Nishiga M, Usami S, Izuhara M, Nakao T, Nishino T, Kita T, Kimura T, Ono K.
Organizer
9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
Place of Presentation
Kyoto
Year and Date
2014-09-12 – 2014-09-14
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[Presentation] MicroRNA-33, embedded in Srebf2 intron, regulate fatty acid synthesis through targeting SREBP-1 in vivo.2014
Author(s)
Nishino T, Horie T, Baba O, Kuwabara Y, YOkode M, Kita T, Kimura T, Ono K.
Organizer
9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
Place of Presentation
Kyoto
Year and Date
2014-09-12 – 2014-09-14
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[Presentation] MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein-2 (Srebp2) regulates Srebp1 in vivo.2014
Author(s)
Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Sowa N, Yahagi N, Shimano H, Hasegawa K, Kume N Yokode M, Kita T, Kimura T, Ono K.
Organizer
The 18th International Vascular Biology Meeting
Place of Presentation
Kyoto
Year and Date
2014-04-14 – 2014-04-14
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[Presentation] MicroRNA-33 deficiency reduces atherosclerotic plaque progression in apoE knockout mice.2014
Author(s)
Baba O, Horie T, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, Horiguchi M, Nakamura T, Chonabayashi K, Hishizawa M, Hasegawa K, Kume N Yokode M, Kita T, Kimura T, Ono K.
Organizer
The 18th International Vascular Biology Meeting
Place of Presentation
Kyoto
Year and Date
2014-04-14 – 2014-04-14
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