2014 Fiscal Year Annual Research Report
Neoatherosclerosisの本態解明と新規治療法の開発
Project/Area Number |
25293182
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Research Institution | Kyoto University |
Principal Investigator |
木村 剛 京都大学, 医学(系)研究科(研究院), 教授 (80359786)
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Co-Investigator(Kenkyū-buntansha) |
尾野 亘 京都大学, 医学(系)研究科(研究院), 准教授 (00359275)
今井 逸雄 京都大学, 医学(系)研究科(研究院), 助教 (10625677)
齋藤 成達 京都大学, 医学(系)研究科(研究院), 助教 (20467484)
西 英一郎 京都大学, 医学(系)研究科(研究院), 准教授 (30362528)
牧山 武 京都大学, 医学(系)研究科(研究院), 助教 (30528302)
塩井 哲雄 京都大学, 医学(系)研究科(研究院), 講師 (50360095)
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Project Period (FY) |
2013-04-01 – 2016-03-31
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Keywords | neoatherosclerosis / 血栓 / ステント |
Outline of Annual Research Achievements |
①BMSおよびDES留置を行った症例でのステント治療部位の解析:ステント留置後の長期フォロー例を中心にデータの蓄積を行い、これらの症例サンプルにおいて詳細な基礎的検討を行っている。 ②BMSおよびDES留置後、VLSTを発症した患者の吸引血栓の病理的分子生物学的検討:17例の早期血栓症(early stent thrombosis; EST 30日以内の発症)、7例の遅発性血栓症 (late ST; LST 31-365日での発症)、24例の超遅発性血栓症 (very late ST; VLST 1年以降の発症)での血栓の性状をさらに検討した。血栓の中の好酸球分画はVLSTでは8.2±5.7%、LSTでは5.5±3.8%、EST4.3±3.0%と、有意にVLSTに多かった。また、血管造影上peri-stent contrast staining (PSS)と呼ばれる所見あるいはstentの不完全な留置を得られた例においては、好酸球分画が有意に高かった。さらにVLSTの病理組織内において、13%に動脈硬化巣の組織の一部を認め、neoatherosclerosisがVLSTの原因をなしている可能性が示唆された。 ③ステント留置後の剖検症例の集積:症例を増加させている。 ④血管内皮を早期に増殖、障害血管の再内皮化をはかるステントの開発:早期の臨床応用を視野に、ウイルスなどのベクターを使用せず、miR-126を局所で過剰発現させるための2本鎖合成RNAを設計した。さらに、この2本鎖合成RNAを乳酸・グリコール酸共重合体(PLGA)ナノ粒子に含有させ、ステントに電気的に均一にコーティングし、局所で徐放化できるステントを開発した。 まず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。
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
①BMSおよびDES留置を行った症例でのステント治療部位の解析:VLSTの頻度は0.1%と非常に低いが、着実に症例を集積している。 ②BMSおよびDES留置後、VLSTを発症した患者の吸引血栓の病理的分子生物学的検討:17例の早期血栓症(early stent thrombosis; EST 30日以内の発症)、7例の遅発性血栓症 (late ST; LST 31-365日での発症)、24例の超遅発性血栓症 (very late ST; VLST 1年以降の発症)での血栓の性状をさらに検討し、疾患の本態解明に近づいている。 ③ステント留置後の剖検症例の集積:冠動脈病理研究レジストリーで集積された病理標本から臨床症例を集積している。 ④血管内皮を早期に増殖、障害血管の再内皮化をはかるステントの開発:miR-126の徐放化ステントをウサギモデルに用い、良好な効果を認めた。
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Strategy for Future Research Activity |
ステントによる冠動脈治療は虚血性心疾患に対する標準的な治療である。薬剤溶出性ステント(Drug eluting stent; DES)の登場により治療後早期の再狭窄率も劇的に改善した。しかしながらDES留置後1年以降に生じる超遅発性ステント血栓症(very late stent thrombosis; VLST)と遠隔期に生じるステント内再狭窄であるlate catch-up現象が重大な問題として残されている。これらの共通の原因としてステント治療後のneoatherosclerosisが注目されているが、この病態解明と治療へ向けて、臨床症例の解析と新規ステントの開発を進めていく。
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Author(s)
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Journal Title
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Journal Title
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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
Eur Heart J Cardiovasc Imaging.
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Kimura T, Shiomi H, Kuribayashi S, Isshiki T, Kanazawa S, Ito H, Ikeda S, Forrest B, Zarins CK, Hlatky MA, Norgaard BL.
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Journal Title
Cardiovasc Interv Ther.
Volume: 30
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Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Cardiac-specific inhibition of kinase activity in calcium/calmodulin-dependent protein kinase kinase-β 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, Ono K.
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Journal Title
PLoS One.
Volume: 9
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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
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Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.2014
Author(s)
Yamada Y, Kinoshita H, Kuwahara K, Nakagawa Y, Kuwabara Y, Minami T, Yamada C, Shibata J, Nakao K, Cho K, Arai Y, Yasuno S, Nishikimi T, Ueshima K, Kamakura S, Nishida M, Kiyonaka S, Mori Y, Kimura T, Kangawa K, Nakao K.
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Journal Title
Cardiovasc Res.
Volume: 104
Pages: 183-93
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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 Coronary 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
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Volume: 7
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Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Predictive Performance of SYNTAX Score II in Patients With Left Main and Multivessel Coronary Artery Disease-analysis of CREDO-Kyoto registry.2014
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Volume: 78
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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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Volume: 16
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Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Relation of contrast-induced nephropathy to long-term mortality after percutaneous coronary intervention.2014
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Abe M, Morimoto T, Akao M, Furukawa Y, Nakagawa Y, Shizuta S, Ehara N, Taniguchi R, Doi T, Nishiyama K, Ozasa N, Saito N, Hoshino K, Mitsuoka H, Toma M, Tamura T, Haruna Y, Kita T, Kimura T.
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Am J Cardiol.
Volume: 114
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Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Anticoagulant and antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention.2014
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Goto K, Ono K, Makiyama T, Nakagawa Y, Furukawa Y, 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, Kimura T
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Am J Cardiol.
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[Journal Article] AMAP1 as a negative-feedback regulator of nuclear factor-κB under inflammatory conditions.2014
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Volume: 4
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[Journal Article] Long-term efficacy and safety outcomes after unrestricted use of drug-eluting stents in patients with acute coronary syndrome: mortality and major bleeding in a single-center registry.2014
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Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Long-term clinical outcomes after everolimus- and sirolimus-eluting coronary stent implantation: final 3-year follow-up of the randomized evaluation of sirolimus-eluting versus everolimus-eluting stent trial.2014
Author(s)
Shiomi H, Kozuma K, Morimoto T, Igarashi K, Kadota K, Tanabe K, Morino Y, Akasaka T, Abe M, Suwa S, Muramatsu T, Kobayashi M, Dai K, Nakao K, Uematsu M, Tarutani Y, Fujii K, Simonton CA, Kimura T; RESET Investigators.
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Journal Title
Circ Cardiovasc Interv.
Volume: 7
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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 vivo2014
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 mice2014
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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