動脈硬化プラーク脆弱化の分子機構の解明と急性冠症候群予測因子の同定

2011 Fiscal Year Annual Research Report

• Project/Area Number: 22390159
• Research Institution: The University of Tokushima
• Principal Investigator: 佐田 政隆 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (80345214)
• Co-Investigator(Kenkyū-buntansha): 添木 武 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 講師 (60393211) ; 平田 恭信 東京大学, 医学部附属病院, 特任准教授 (70167609)
• Keywords: 循環器・高血圧 / 動脈硬化 / 急性冠症候群 / プラーク破裂 / 血管新生

Research Abstract

急性冠症候群の多くは,軽度内腔を狭窄する動脈硬化プラークの破裂やびらんを基礎とした血栓性閉塞を原因とする。この動脈硬化プラーク脆弱化の分子機構を明らかにするために、臨床材料ならびに動物モデルを用いて検討した。
(1)動脈硬化の進展における心臓周囲脂肪組織の役割について、臨床材料を用いて検討した。心臓手術中に36名の冠動脈疾患患者ならびに46名の非冠動肺疾患患者(主として心臓弁膜症)患者から、心臓周囲脂肪組織ならびに皮下脂肪を採取した。冠動脈疾患患者では、非冠動脈疾患に比較して、心臓周囲脂肪組織における浸潤マクロファージ数が増加しており、その極性が相対的にM1側へシフトしていた。また、このような変化は、MCP-1,TNFα、IL-1βなどの炎症性サイトカイン、TLRなどの病原体センサーの発現の亢進を伴っていた。興味深いことには、皮下脂肪に関しては、冠動脈疾患患者と非冠動脈疾患患者で違いは認められなかった。また、冠動脈疾患患者においても、内胸動脈周囲脂肪組織では、皮下脂肪と同様に炎症性の変化亢進してしなかった。心臓周囲脂肪組織における慢性炎症が、冠動脈疾患の病態に関与していること、周囲脂肪組織の性状によって内胸動脈が動脈硬化性ストレスから保護されていることが示唆された。
(2)冠動脈疾患患者の冠状静脈洞採血において、HMGB1の濃度が亢進していた。その病態生理学的意義を明らかにするため、遺伝子欠損マウスと骨髄移植を用いた実験を行った。血管傷害後血中のHMGB1濃度が亢進することと、HMGB1-DNA複合体がマクロファージのTLR9を介して病的炎症を惹起することから、HMGB1-DNA複合体が動脈硬化の病態に関与することが明らかとなった。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

予定どおりの研究が進行し、成果が得られ、論文として発表して高い評価を得ている。

Strategy for Future Research Activity

進行した動脈硬化病変モデルにおいて,不安定プラークに認められる遺伝子発現とその制御因子を探求する。
モデル動物を用いて得られた知見が、実際に動脈硬化患者で生じているかどうかを臨床材料を用いて検討する。その解析のために、研究体制は確立しており、倫理委員会の承認なども得ている。

Research Products

• [Journal Article] Aliskiren in combination with valsartan exerts synergistic protective effects against ventricular remodeling after myocardial infarction in mice (2012)
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  • Journal Title: Hypertens Re Volume: 35 Pages: 62-69
  • DOI: doi:10.1038/hr.2011.136
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• [Journal Article] The Radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation (2012)
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  • Journal Title: Diabetes Volume: (In press)
  • DOI: 10.2337/db11-1182
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• [Journal Article] Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue (2011)
  • Author(s): Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M
  • Journal Title: J Am Coll Cardiol Volume: 58 Pages: 248-255
  • DOI: doi:10.1016/j.jacc.2011.01.048
  • Peer Reviewed
• [Journal Article] Enhanced inflammation in epicardial fat in patients with coronary artery disease (2011)
  • Author(s): Hirata Y, Kurobe H, Akaike M, Chikugo F, Hori T, Bando Y, Nishio C, Higashida M, Nakaya Y, Kitagawa T, Sata M.
  • Journal Title: Int Heart J Volume: 52 Pages: 139-142.
  • DOI: doi:10.1536/ihj.52.139
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• [Journal Article] Serial imaging changes during treatment of Takayasu arteritis with pulmonary artery stenosis (2011)
  • Author(s): Kusunose K, Yamada H, Tomita N, Nishio S, Niki T, Yamaguchi K, Koshiba K, Yagi S, Taketani Y, Iwase T, Soeki T, Wakatsuki T, Akaike M, Sata M.
  • Journal Title: Int J Cardiol. Volume: 148 Pages: e47-e50
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• [Journal Article] Acute hemodynamic effects of adaptive servo ventilation in patients with pulmonary hypertension (2011)
  • Author(s): Yagi S, Akaike M, Iwase T, Kusunose K, Niki T, Yamaguchi K, Koshiba K, Taketani Y, Tomita N, Yamada H, Soeki T, Wakatsuki T, Sata M
  • Journal Title: Int J Cardiol. Volume: 148 Pages: 125-127
  • DOI: doi:10.1016/j.ijcard.2011.01.074
  • Peer Reviewed
• [Journal Article] High plasma aldosterone concentration is a novel risk factor of cognitive impairment in patients with hypertension (2011)
  • Author(s): Yagi S, Akaike M, Aihara KI, Iwase T, Yoshida S, Sumitomo-Ueda Y, Ikeda Y, Ishikawa K, Matsumoto T, Sata M
  • Journal Title: Hypertens Res. Volume: 34 Pages: 74-78
  • DOI: doi:10.1038/hr.2010.179
  • Peer Reviewed
• [Journal Article] Development of small-diameter vascular grafts based on silk fibroin fibers from bombyx mori for vascular regeneration (2011)
  • Author(s): Nakazawa, Y., et al
  • Journal Title: J Biomater Sci Polym Ed Volume: 22 Pages: 195-206
  • DOI: 10.1163/092050609X12586381656530
  • Peer Reviewed
• [Journal Article] Validation of longitudinal peak systolic strain by speckle tracking echocar diography with visual assessment and myocardial perfusion SPECT in patients with regional asynergy (2011)
  • Author(s): Kusunose, K., et al
  • Journal Title: Circ J Volume: 75 Pages: 141-147
  • DOI: 10.1253/circj.CJ-10-0551
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• [Journal Article] Hic-5 deficiency enhances mechanosensitive apoptosis and modulates vascular remodeling (2011)
  • Author(s): Kim-Kaneyama, et al
  • Journal Title: J Mol Cell Cardiol Volume: 50 Pages: 77-86
  • DOI: 10.1016/j.bbrc.2008.09.051
  • Peer Reviewed
• [Journal Article] Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors (2011)
  • Author(s): Ise, T., et al
  • Journal Title: Hypertens Res Volume: 34 Pages: 225-231
  • DOI: 10.1038/hr.2010.211
  • Peer Reviewed
• [Journal Article] Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice (2011)
  • Author(s): Tanaka, K., et al
  • Journal Title: Atherosclerosis Volume: 215 Pages: 366-373
  • DOI: 10.1016/j.atherosclerosis.2011.01.016
  • Peer Reviewed
• [Journal Article] Bosentan improves systemic sclerosis-related peripheral circulation insufficiency (2011)
  • Author(s): Yagi, S, et al
  • Journal Title: Int J Cardiol Volume: 147 Pages: 472-475
  • DOI: 10.1016/j.ijcard.2011.01.025
  • Peer Reviewed
• [Journal Article] Activation of peroxisome proliferator-activated receptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets (2011)
  • Author(s): Hashizume, S, et al
  • Journal Title: J Atheroscler Thromb Volume: 18 Pages: 138-147
  • DOI: 10.5551/jat.5868
  • Peer Reviewed
• [Journal Article] Synergistic protection against vascular inflammation with a calcium channel blocker and a statin (2011)
  • Author(s): Hirata, Y, et al
  • Journal Title: Hypertens Res Volume: 34 Pages: 441-442
  • DOI: 10.1038/hr.2010.275
  • Peer Reviewed
• [Journal Article] Removal of pinched-off central venous catheter (2011)
  • Author(s): Kusunose, K, et al
  • Journal Title: Heart Asia Volume: 3 Pages: 32
  • DOI: 10.1136/ha.2009.001321
  • Peer Reviewed
• [Journal Article] Chronic inflammation and atherosclerosis : A critical role for renin angiotensin system that is activated by life-style related diseases (2011)
  • Author(s): Sata, M, et al
  • Journal Title: Inflamm Regen Volume: 31 Pages: 245-255
  • DOI: 10.2492/inflammregen.31.245
  • Peer Reviewed
• [Journal Article] Effect of low-dose (1 mg/day) pitavastatin on left ventricular diastolic function and albuminuria in patients with hyperlipidemia (2011)
  • Author(s): Yagi, S, et al
  • Journal Title: Am J Cardiol Volume: 107 Pages: 1644-1649
  • DOI: 10.1016/j.amjcard.2011.01.054
  • Peer Reviewed
• [Journal Article] Ventricular tachycardia in cardiac sarcoidosis controlled by radiofrequency catheter ablation (2011)
  • Author(s): Bando, M, et al
  • Journal Title: Intern Med Volume: 50 Pages: 1201-1206
  • DOI: 10.2169/internalmedicine.49.3812
  • Peer Reviewed
• [Journal Article] Pre-clinical data on the role of mineralocorticoid receptor antagonists in reversing vascular inflammation (2011)
  • Author(s): Yagi, S, et al
  • Journal Title: Eur Heart J Suppl Volume: 13 Pages: B15-B20
  • DOI: 10.1093/eurheartj/sur012
  • Peer Reviewed
• [Journal Article] Preparation of double-raschel knitted silk vascular grafts and evaluation of short-term function in a rat abdominal aorta (2011)
  • Author(s): Yagi, T, et al
  • Journal Title: J Artif Organs Volume: 14 Pages: 89-99
  • DOI: 10.1007/s10047-011-0554-z
  • Peer Reviewed
• [Journal Article] Observation of short-term atorvastatin-induced changes in coronary arterial plaque properties using integrated backscatter intravascular ultrasound in a patient (2011)
  • Author(s): Yamaguchi, K, et al
  • Journal Title: JC Cases Volume: 3 Pages: e111-e114
  • DOI: 10.1016/j.jccase.2011.03.007
  • Peer Reviewed
• [Journal Article] Relationships among hyperuricemia, metabolic syndrome, and endothelial function (2011)
  • Author(s): Tomiyama, H, et al
  • Journal Title: Am J Hypertens Volume: 24 Pages: 770-774
  • DOI: 10.1038/ajh.20011.55
  • Peer Reviewed
• [Journal Article] Comparison of chronic-stage histopathological findings among 3 coronary stents implanted in the same patient (2011)
  • Author(s): Niki, T, et al
  • Journal Title: Int J Cardiol Volume: 150 Pages: e25-e27
  • DOI: 10.1016/j.ijcard.2009.08.032
  • Peer Reviewed
• [Journal Article] A patient who developed toe necrosis due to poor blood circulation after an interdigital tick bite (2011)
  • Author(s): Yamazaki, H, et al
  • Journal Title: JC Cases Volume: 4 Pages: e106-e109
  • DOI: 10.1016/j.jccase.2011.06.005
  • Peer Reviewed
• [Journal Article] A synthetic prostacycline agonist, ONO-1301, ameliorates ventricular remodeling after acute myocardial infarction via up-regulation of HGF in rat (2011)
  • Author(s): Hirata, Y, et al
  • Journal Title: Biomed Aging Pathol Volume: 1 Pages: 90-96
  • DOI: 10.1016/j.biomag.2011.06.004
  • Peer Reviewed
• [Journal Article] Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability (2011)
  • Author(s): Soeki, T, et al
  • Journal Title: J Cardiol Volume: 58 Pages: 151-157
  • DOI: 10.1016/j.jjcc.2011.04.005
  • Peer Reviewed
• [Journal Article] High phosphate diet reduces atherosclerosis formation in apolipoprotein E-deficient mice (2011)
  • Author(s): Shiota, A, et al
  • Journal Title: J Clin Biochem Nutr Volume: 49 Pages: 109-114
  • DOI: 10.3164/jcbn.10-150
  • Peer Reviewed
• [Journal Article] Reproducibility and diagnostic accuracy of three-layer speckle tracking echocardiography in a swine chronic ischemia model (2011)
  • Author(s): Kimura, K, et al
  • Journal Title: Echocardiography Volume: 28 Pages: 1148-1155
  • DOI: 10.111/j.1540.-888175.2011.01517
  • Peer Reviewed
• [Journal Article] Local persistent hypercoagulability after sirolimus-eluting stent implantation in patients with stable angina (2011)
  • Author(s): Yamaguchi, K, et al
  • Journal Title: Int J Cardiol Volume: 153 Pages: 272-276
  • DOI: 10.1016/j.ijcard.2010.08.014
  • Peer Reviewed
• [Journal Article] Ezetimibe monotherapy ameliorates vascular function in patients with hypercholesterolemia through decreasing oxidative stress (2011)
  • Author(s): Kurobe, H, et al
  • Journal Title: J Atheroscler Thromb Volume: 18 Pages: 1080-1089
  • DOI: doi:10.5551/jat.9548
  • Peer Reviewed
• [Journal Article] A synthetic prostacyclin agonist thrombozane synthase inhibitory activity, ONO-1301, protects myocardium from ischemia/reperfusion injury (2011)
  • Author(s): Hirata, Y, et al
  • Journal Title: Eur J Pharmacol Volume: 674 Pages: 352-358
  • DOI: 10.1016/j.biopha.2009.09.003
  • Peer Reviewed
• [Journal Article] The ATP-binding cassette transporter ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response (2011)
  • Author(s): Higashikuni, Y, et al
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Pages: 654-661
  • DOI: 10.1161/ATVBAHA.110.211755
  • Peer Reviewed
• [Journal Article] Intensive glucose lowering in cardiovascular risk management (2011)
  • Author(s): Shimabukuro, M, et al
  • Journal Title: Circ J Volume: 76 Pages: 593-595
  • DOI: 10.1253/circj.CJ-12-0062
  • Peer Reviewed
• [Presentation] Detection of. Cardiac Involvement in Patients with Sarcoidosis Using Cardiac Magnetic Resonance (2011)
  • Author(s): Iwase, T., et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Effects of Telmisartan on Inflammatory Cytokines and Coronary Plaque Component Assessed by Integrated Backscatter Intravascular Ultrasound in Hypertensive Patients (2011)
  • Author(s): Yamaguchi, K., et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Ultrasonic Tissue Characterization of Carotid Artery Plaque using High-resolution Integrated Backscatter Imaging ; Validation Study with Histological Correlation (2011)
  • Author(s): Bando, M., et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Pentraxin 3 is a Local Inflammatory Maker in Atrial Fibrillation (2011)
  • Author(s): Soeki, T., et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] HMGB1 Signal via TLR9 Plays Critical Role in Vascular Remodeling (2011)
  • Author(s): Higashida, M., et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] Single-Beat Assessment of Left Ventricular Systolic and Diastolic Function during Atrial Fibrillation using Myocardial Strain and Strain Rate (2011)
  • Author(s): Kusunose, K., et al
  • Organizer: AHA Scientific Sessions 2011
  • Place of Presentation: Orange Country Conversion Center, Orlando, Florida
  • Year and Date: 20111112-20111116
• [Presentation] 心臓周囲脂肪におけるインフラマゾームの病態的意義 (2011)
  • Author(s): 佐藤寛美, 他
  • Organizer: 第32回日本肥満学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20110923-20110924
• [Presentation] テルミサルタンは、beyond AT1R作用により動脈硬化抑制作用を示す (2011)
  • Author(s): 塩田あすか, 他
  • Organizer: 第32回日本肥満学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20110923-20110924
• [Presentation] エイコサペンクエン酸は高脂血症において脂肪酸構成を変化させ、血管内皮機能を改善する (2011)
  • Author(s): 山川研, 他
  • Organizer: 第32回日本肥満学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20110923-20110924
• [Presentation] Heparin Cofactor II Promotes Angiogenesis via an AMPK-eNOS Signaling Pathway (2011)
  • Author(s): Ikeda, Y., et al
  • Organizer: American Heart Association HBPR 2011
  • Place of Presentation: Walt Disney, World Dolphin Resort, Orlando, Florida
  • Year and Date: 20110920-20110924
• [Presentation] Impact of abdominal obesity and insulin resistance on cardiovascular events in Japanese obesity-endemic area : Okinawa Tomishiro Cohort Study (2011)
  • Author(s): Shimabukuro, M., et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] Long-term local inflammatory and coagulative responses after coronary artery stenting with drug-eluting stent (2011)
  • Author(s): Wakatsuki, T., et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] Elevated concentration of pentraxin 3 is associated with local inflammation in atrial fibrillation (2011)
  • Author(s): Soeki, T., et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] Deterioration of right ventricular myocardial systolic function in monocrotaline-induced pulmonary arterial hypertension canine model : echocardiographic evaluation by 2D speckle tracking (2011)
  • Author(s): Nishio, S., et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] GLP-1 receptor agonist attenuates vascular remodeling after endovascular injury (2011)
  • Author(s): Hirata, Y., et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831
• [Presentation] HMGB1/TLR9 pathway plays a critical role in chronic inflammation and vascular remodeling after endovascular injury (2011)
  • Author(s): Higashida, M., et al
  • Organizer: ESC Congress 2011
  • Place of Presentation: Paris Nord Villepinte exhibition center, Paris
  • Year and Date: 20110827-20110831