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Molecular mechanisms of uric acid for promoting atherosclerosis

Research Project

Project/Area Number 18K08418
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54020:Connective tissue disease and allergy-related
Research InstitutionTeikyo University

Principal Investigator

Kono Hajime  帝京大学, 医学部, 教授 (60585074)

Co-Investigator(Kenkyū-buntansha) 本田 善一郎  お茶の水女子大学, 保健管理センター, 教授 (70238814)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords動脈硬化 / 尿酸 / AMPK / インフラマソーム / HIF-1α / ミトコンドリア活性酸素 / IL-1 / 自然炎症 / mTOR
Outline of Final Research Achievements

Uric acid is supposed but not yet determined to be associated with atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. The secretion of IL-1β from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.

Academic Significance and Societal Importance of the Research Achievements

高尿酸血症は動脈硬化における増悪因子と想定されており、実際痛風患者では心血管イベントが高頻度に発生する。しかし動脈硬化を阻止するために尿酸を低下させるのが良いのかどうかは明らかではなかった。我々はマウスと細胞を用いた基礎実験において尿酸が炎症を引き起こし、動脈硬化を促進させる事を解明した。また、その分子機序も明らかとなった。本研究の結果、動脈硬化の進展阻止において尿酸降下療法の裏付けが得られ、新たな治療介入点も明らかとなった。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (6 results)

All 2020 2019 2018

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 2 results)

  • [Journal Article] Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation2020

    • Author(s)
      Kimura Yoshitaka、Yanagida Tamiko、Onda Akiko、Tsukui Daisuke、Hosoyamada Makoto、Kono Hajime
    • Journal Title

      Arteriosclerosis, Thrombosis, and Vascular Biology

      Volume: 40 Issue: 3 Pages: 570

    • DOI

      10.1161/atvbaha.119.313224

    • URL

      https://pure.teikyo.jp/en/publications/a2d0ff2b-97a2-4b43-a399-4d0944a1a2fe

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Recurrence of disease following organ transplantation in autoimmune liver disease and systemic lupus erythematosus2020

    • Author(s)
      Tanaka Atsushi、Kono Hajime、Leung Patrick S.C.、Gershwin M. Eric
    • Journal Title

      Cellular Immunology

      Volume: 347 Pages: 104021-104021

    • DOI

      10.1016/j.cellimm.2019.104021

    • Related Report
      2019 Research-status Report
  • [Journal Article] Decrease in MPO-ANCA after administration of benralizumab in eosinophilic granulomatosis with polyangiitis2019

    • Author(s)
      Takenaka Kenchi、Minami Tomoko、Yoshihashi Yoko、Hirata Shinya、Kimura Yoshitaka、Kono Hajime
    • Journal Title

      Allergology International

      Volume: 68 Issue: 4 Pages: 539-540

    • DOI

      10.1016/j.alit.2019.04.006

    • NAID

      130007733090

    • ISSN
      1323-8930, 1440-1592
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacies of atovaquone, pentamidine, and trimethoprim/sulfamethoxazole for the prevention of Pneumocystis jirovecii pneumonia in patients with connective tissue diseases2019

    • Author(s)
      Kitazawa Takatoshi、Seo Kazunori、Yoshino Yusuke、Asako Kurumi、Kikuchi Hirotoshi、Kono Hajime、Ota Yasuo
    • Journal Title

      Journal of Infection and Chemotherapy

      Volume: 25 Issue: 5 Pages: 351

    • DOI

      10.1016/j.jiac.2019.01.005

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] A patient presenting with isolated hematuria and renal dysfunction as rare manifestation of cryoglobulinemic glomerulonephritis in the course of autoimmune diseases including Sjögren's syndrome2018

    • Author(s)
      Yamanaka Masaki、Fujigaki Yoshihide、Kono Hajime、Nagura Michito、Arai Shigeyuki、Tamura Yoshifuru、Ota Tatsuru、Shibata Shigeru、Kondo Fukuo、Yamaguchi Yutaka、Uchida Shunya
    • Journal Title

      CEN Case Reports

      Volume: 7 Issue: 2 Pages: 211

    • DOI

      10.1007/s13730-018-0329-y

    • URL

      https://pure.teikyo.jp/en/publications/8e3fb2ad-22b2-4394-a25b-e4fcd08e72c9

    • Related Report
      2018 Research-status Report
  • [Journal Article] Evidence-based clinical practice guideline for adult Still’s disease2018

    • Author(s)
      Mimura T, Kondo Y, et al.
    • Journal Title

      Mod Rheumatol, in press

      Volume: 28 Issue: 5 Pages: 736

    • DOI

      10.1080/14397595.2018.1465633

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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