High risk coronary plaque for acute myocardial infarction: who is a culprit of increased thrombogenicity

• Project/Area Number: 19K16560
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Maekawa Kazunari 宮崎大学, 医学部, 助教 (30754171)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2021: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
• Keywords: 動脈硬化 / 血栓症 / マクロファージ / 低酸素 / 心筋梗塞 / 冠動脈 / 血液凝固活性 / 血栓 / プラーク / 動脈血栓

Outline of Research at the Start

急性心筋梗塞は、冠動脈のプラークが破裂することで血栓ができ、冠動脈が詰まることで発症する。しかし、プラークが破裂しても血栓が小さく、心筋梗塞に到らない場合が少なからずあることが判明し、プラークの血栓形成能が重要視されてきている。申請者らはプラーク内では血液凝固を促進する働きが強く、逆に血栓を溶かす働きが弱いことを明らかにしてきた。また申請者は、血液供給の乏しいプラーク中心部に特に血栓形成を促進する物質が多くみられることから、プラーク内の低酸素環境が血栓形成を促進していると推察した。
本研究では、①血栓促進物質の生成における低酸素の関与、②低酸素が血栓促進物質の生成を促進する機序、を明らかにする。

Outline of Final Research Achievements

The purpose of this study is (1) the involvement of hypoxia in the expression of tissue factor in coronary artery plaques, and (2) the molecular biological mechanisms by which hypoxia promotes thrombus formation.
(1) In a study using coronary artery specimens from autopsy cases, macrophages were more abundant in “vulnerable plaques” than in “stable plaques,” and the expression and localization of tissue factor and hexokinase 2 in plaques were associated with macrophages. (2) In cultured macrophages, hypoxia increased the coagulation activity of cells induced by inflammatory stimulation. The effect was also abolished by inhibition of glycolysis.
Based on the above, hypoxia-induced glycolytic metabolism was considered to contribute to plaque thrombus formation.

Academic Significance and Societal Importance of the Research Achievements

急性心筋梗塞の原因となる動脈硬化は喫煙、ストレス、高血圧、脂質異常や糖尿病により進展することがしられている。さらにプラークの血栓形成能を増大させる機序が明らかとなれば、予防的介入の選択肢が広がり、国民の健康に貢献できる可能性が期待される。

Research Products

• [Journal Article] Upregulated Kynurenine Pathway Enzymes in Aortic Atherosclerotic Aneurysm: Macrophage Kynureninase Downregulates Inflammation (2021)
  • Author(s): Nishimura Masanori、Yamashita Atsushi、Matsuura Yunosuke、Okutsu Junichi、Fukahori Aiko、Hirata Tsuyoshi、Nishizawa Tomohiro、Ishii Hirohito、Maekawa Kazunari、Nakamura Eriko、Kitamura Kazuo、Nakamura Kunihide、Asada Yujiro
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 11 Pages: 1214-1240
  • DOI: 10.5551/jat.58248
  • NAID: 130008110108
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-11-01
  • Peer Reviewed / Open Access
• [Journal Article] Pathological features of ruptured coronary plaque and thrombus interfaces: fibrin and von Willebrand factor as platelet scaffolds on rupture sites (2021)
  • Author(s): Yamashita A, Nishihira K, Gi T, Maekawa K, Hatakeyama K, Horiuchi S, Wada K, Shibata Y, Asada Y.
  • Journal Title: Thromb Haemost. Volume: 121 Issue: 02 Pages: 234-241
  • DOI: 10.1055/s-0040-1716539
  • Peer Reviewed / Open Access
• [Journal Article] Translocator protein imaging with 18F-FEDAC-positron emission tomography in rabbit atherosclerosis and its presence in human coronary vulnerable plaques. (2021)
  • Author(s): Maekawa K, Tsuji AB, Yamashita A, Sugyo A, Katoh C, Tang M, Nishihira K, Shibata Y, Koshimoto C, Zhang MR, Nishii R, Yoshinaga K, Asada Y
  • Journal Title: Atherosclerosis Volume: 337 Pages: 7-17
  • DOI: 10.1016/j.atherosclerosis.2021.10.003
  • Peer Reviewed / Open Access
• [Journal Article] Intracellular glutamine level determines vascular smooth muscle cell-derived thrombogenicity. (2021)
  • Author(s): Koyama S, Yamashita A, Matsuura Y, Saito Y, Maekawa K, Gi T, Kitamura K, Asada Y
  • Journal Title: Atherosclerosis Volume: 328 Pages: 62-73
  • DOI: 10.1016/j.atherosclerosis.2021.05.012
  • Peer Reviewed / Open Access
• [Journal Article] Higher lactate and purine metabolite levels in erythrocyte-rich fresh venous thrombus: Potential markers for early deep vein thrombosis (2019)
  • Author(s): Maekawa Kazunari、Sugita Chihiro、Yamashita Atsushi、Moriguchi-Goto Sayaka、Furukoji Eiji、Sakae Tatefumi、Gi Toshihiro、Hirai Toshinori、Asada Yujiro
  • Journal Title: Thrombosis Research Volume: 177 Pages: 136-144
  • DOI: 10.1016/j.thromres.2019.03.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Coronary high-signal-intensity plaques on T(1)-weighted magnetic resonance imaging reflect intraplaque hemorrhage (2019)
  • Author(s): Kuroiwa Y, Uchida A, Yamashita A, Miyati T, Maekawa K, Gi T, Noguchi T, Yasuda S, Imamura T, Asada Y
  • Journal Title: Cardiovasc Pathol Volume: 40 Pages: 24-31
  • DOI: 10.1016/j.carpath.2019.01.002
  • Peer Reviewed / Open Access
• [Presentation] 炎症と低酸素環境は冠動脈プラークの血栓形成能を相加的に亢進させる (2022)
  • Author(s): 前川和也、山下篤、松浦祐之介、西平賢作、中村恵理子、西東洋一、菰原義弘、畠山金太、海北幸一、柴田剛徳、浅田祐士郎
  • Organizer: 日本血栓止血学会
• [Presentation] Translocator proteinを標的としたハイリスク冠動脈プラークの検出. (2021)
  • Author(s): 前川和也、辻 厚至、山下 篤、須堯 綾、加藤千恵次、Minghui Tang、西平賢作、柴田剛徳、越本知大、Ming-Rong Zhang、西井龍一、吉永恵一郎、浅田祐士郎.
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] ontribution of fibrin and von Willebrand factor to platelet adhesion on ruptured atherosclerotic plaque in acute myocardial infarction. (2020)
  • Author(s): Yamashita A, Nishihira K, Maekawa K, Gi T, Saki Horiuchi, Hatakeyama K, Shibata Y, Asada Y.
  • Organizer: 28th Congress of International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Presentation] 破裂性冠動脈プラークの血小板粘着にフィブリンやフォンウィルブランド因子が関与する. (2020)
  • Author(s): 山下 篤、西平賢作、前川和也、魏 峻洸、畠山金太、柴田剛徳、浅田祐士郎
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] Histological features of ruptured plaque and thrombus interface in acute myocardial infarction. (2019)
  • Author(s): Yamashita A, Nishihira K, Maekawa K, Gi T, Hatakeyama K, Shibata Y, Asada Y
  • Organizer: ATVB/PVD2019
  • Int'l Joint Research
• [Presentation] Quantitative susceptibility mapping on magnetic resonance imaging distinguishes intraplaque hemorrhage and iron deposition from calcification in carotid atherosclerosis. (2019)
  • Author(s): Maekawa K, Yamashita A, Azuma M, Enzaki M, Yokogami K, Takeshima H, Wang Y, Hirai T, Asada A.
  • Organizer: ATVB/PVD2019
  • Int'l Joint Research
• [Presentation] キヌレニン代謝酵素インドールアミン2,3ジオキシゲナーゼ1の急性冠症候群における関与. (2019)
  • Author(s): 山下 篤、渡邊裕貴、前川和也、北村和雄、浅田祐士郎
  • Organizer: 第108回日本病理学会総会
• [Presentation] 頸動脈プラークの組織像と磁気共鳴画像における定量的磁化率マッピングとの対比. (2019)
  • Author(s): 前川和也、東 美菜子、山下 篤、平井俊範、浅田祐士郎
  • Organizer: 第108回日本病理学会総会
• [Presentation] Pathological features of ruptured atherosclerotic plaque and thrombus interface in acute myocardial infarction (2019)
  • Author(s): Yamashita A, Nishihira K, Maekawa K, Gi T, Hatakeyama K, Shibata Y, Asada Y
  • Organizer: 27th Congress of International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Presentation] Coronary high-signal-intensity plaques on T1-weighted magnetic resonance imaging reflect intraplaque hemorrhage: A novel marker for plaque instability and thrombogenic potential. (2019)
  • Author(s): Kuroiwa Y, Uchida A, Yamashita A, Miyati T, Maekawa K, Gi T, Noguchi T, Yasuda S, Imamura T, Asada Y
  • Organizer: 27th Congress of International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Book] 新臨床静脈学 (2019)
  • Author(s): 前川和也、浅田祐士郎
  • Total Pages: 520
  • Publisher: メジカルビュー社
  • ISBN: 9784758319614