Molecular mechanism of coronary microcirculation injury via endothelial Toll-like receptor in acute myocardial infarction

• Project/Area Number: 16K08668
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Ehime University
• Principal Investigator: Kurata Mie 愛媛大学, プロテオサイエンスセンター, 講師 (80423440)
• Research Collaborator: Masumoto Junya ; Kaneko Naoe
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 急性心筋梗塞 / NETs / 内皮障害 / 人体病理 / no-reflow現象 / 好中球 / Toll様受容体 / 冠微小循環障害 / 内皮細胞障害 / コムギ胚芽タンパク合成系

Outline of Final Research Achievements

In acute myocardial infarction, there may occur a so-called microcirculatory disorder (no-reflow phenomenon) in which sufficient blood perfusion can not be obtained in the myocardium although the occlusion site is released. Applicants hypothesized that this phenomenon involves a mechanism by which neutrophils capture foreign pathogens by releasing a complex of their own nucleic acid and intracellular protein: neutrophil extracellular traps (NETs). We demonstrated NETs at the lesion site in acute myocardial infarction at autopsy. In addition, in order to clarify the endothelial receptor of nucleic acid complex NETs, we synthesized TLR in cell-free wheat germ system and revealed that it binds to known ligands.

Academic Significance and Societal Importance of the Research Achievements

No-reflow現象の主たる病理像である内皮傷害は形態的検討はなされているもののその詳細な細胞伝達機構は未だ明らかではない。かしそれらの結果は依然no-reflow 現象を抑制する治療薬開発には結びついておらず、現在唯一のエビデンスを持った薬剤は血管拡張薬という対症療法のみである。いま、あらたな治療戦略が求められており、本研究がその一助となる可能性がある。

Research Products

• [Journal Article] Proteomics-based analysis of lung injury-induced proteins in a mouse model of common bile duct ligation. (2017)
  • Author(s): Sakaue T, Shikata F, Utsunomiya K, Fukae S, Kurata M, Nakaoka H, Okazaki M, Kawanishi Y, Kojima A, Higashiyama S, Izutani H.
  • Journal Title: Surgery Volume: 印刷中 Issue: 6 Pages: 1525-1535
  • DOI: 10.1016/j.surg.2016.12.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasma thrombin-cleaved osteopontin as a potential biomarker of acute atherothrombotic ischemic stroke. (2017)
  • Author(s): Ozaki S, Kurata M, Kumon Y, Matsumoto S, Tagawa M, Watanabe H, Ohue S, Higaki J, Ohnishi T
  • Journal Title: Hypertens Res. Volume: 40 Issue: 1 Pages: 61-66
  • DOI: 10.1038/hr.2016.110
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histological assessment of the efficacy of drug-eluting beads in portal tumor thrombosis of hepatocellular carcinoma. (2016)
  • Author(s): Imai Y, Hirooka M, Koizumi Y, Nakamura Y, Watanabe T, Yoshida O, Tokumoto Y, Takeshita E, Abe M, Tanaka H, Kurata M, Kitazawa S, Hiasa Y.
  • Journal Title: Radiol Case Rep. Volume: 12 Issue: 1 Pages: 179-184
  • DOI: 10.1016/j.radcr.2016.11.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nod2-Nodosome in a Cell-Free System: Implications in Pathogenesis and Drug Discovery for Blau Syndrome and Early-Onset Sarcoidosis. (2016)
  • Author(s): Iwasaki T, Kaneko N, Ito Y, Takeda H, Sawasaki T, Heike T, Migita K, Agematsu K, Kawakami A, Morikawa S, Mokuda S, Kurata M, Masumoto J.
  • Journal Title: The Scientific World Journal Volume: － Pages: 2597376-2597376
  • DOI: 10.1155/2016/2597376
  • NAID: 120005819501
  • Peer Reviewed / Open Access
• [Journal Article] Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice. (2016)
  • Author(s): Pei Z, Okura T, Nagao T, Enomoto D, Kukida M, Tanino A, Miyoshi K, Kurata M, Higaki J.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 28882-28894
  • DOI: 10.1038/srep28882
  • Peer Reviewed / Open Access
• [Presentation] ループス腎炎と血管炎: ISN/RPS分類概説と腎炎関連自己抗体 (2018)
  • Author(s): 倉田美恵
  • Organizer: 日本病理学会 総会
• [Presentation] 急性心筋梗心におけるNeutrophil Extracellular TrapsとASCの分布 (2017)
  • Author(s): 南渕杜萌, 井坂 光佑，森川紳之祐, 金子直恵, 伊藤有紀, 中野直子, 倉田美恵, 増本純也
  • Organizer: 日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-27
• [Presentation] THE PATHOLOGICAL DISTRIBUTION OF NEUTROPHIL EXTRACELLULAR TRAPS CORRELATE WITH IMPAIRED MYOCARDIAL REPERFUSION IN PATIENTS WITH ST ELEVATED MYOCARDIAL INFARCTION (2017)
  • Author(s): Mie Kurata, Tomo Nabuchi, Kosuke Isaka, Anouschka Auter, Heleen M.M. van Beusekom, Yuki Ito, Takahiro Yamamoto, Naoko Nakano, Takahiro Yamamoto and Junya Masumoto
  • Organizer: 18th International Vasculitis and ANCA Workshop
  • Place of Presentation: 東京
  • Year and Date: 2017-03-25
  • Int'l Joint Research
• [Presentation] The Pathological Distribution of Neutrophil Extracellular Traps in Patients with ST Elevated Myocardial Infarction by Autopsy Hearts (2017)
  • Author(s): Mie Kurata, Tomo Nabuchi
  • Organizer: 日本循環器学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] 急性心筋梗心におけるNeutrophil Extracellular Trapsの分布 (2017)
  • Author(s): 南渕 杜萌, 倉田 美恵, 増本 純也
  • Organizer: 第58回日本組織細胞化学会総会・学術集会
• [Book] 血管炎（第2版） (2018)
  • Author(s): 倉田美恵
  • Total Pages: 622
  • Publisher: 日本臨牀