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Kv1.5 channel mediates monosodium urate-induced activation of NLRP3 inflammasome in macrophages and arrhythmogenic effects of urate on cardiomyocytes

Research Project

Project/Area Number 18K08074
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionTottori University

Principal Investigator

LI Peili  鳥取大学, 医学部, 特命助教 (40464292)

Co-Investigator(Kenkyū-buntansha) 久留 一郎  鳥取大学, 医学(系)研究科(研究院), 教授 (60211504)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsKv1.5 / NLRP3 inflammasome / Monosodium urate / atrial fibrillation / Heat shock protein / 尿酸結晶 / K efflux / heat shock protein 70 / Kv1.5 channel / gout / macrophage / NLRP3 inflammsome / monosodium urate / inflammasome / 心房細動
Outline of Final Research Achievements

Gout is commonly found in patients with atrial fibrillation (AF). We found that a K+ channel Kv1.5 regulates monosodium urate crystal (MSU)-induced NLRP3 inflammasome activation and electrical remodeling in mouse macrophages J774.1 and atrial myocytes HL-1. Kv1.5 inhibitor or knockdown of Kv1.5 by siRNAs suppressed the NLRP3 inflammasome activation. MSU increased expression of Hsp70, and Kv1.5. a siRNA against Hsp70 were suppressed but heat shock activated the NLRP3 inflammasome in MSU-stimulated J774.1 cells. Incubations of HL-1 cells with the conditioned medium (CM) from MSU-stimulated macrophages activated the NLRP3 inflammasome and enhanced Kv1.5 protein expression with increased Kv1.5-mediated currents that shortened action potential duration in HL-1 cells. These responses were abolished by DPO-1 and a siRNA against Kv1.5. These results indicate that Kv1.5 regulates MSU-induced NLRP3 inflammasome activation in macrophages and electrical remodeling in HL-1 cells.

Academic Significance and Societal Importance of the Research Achievements

高尿酸血症や痛風による炎症又心房細動に対する新規治療薬および治療法開発の重要性は高齢化に伴い益々高まっており、NLRP3インフラマソーム活性化による自然免疫に関する研究は今後最も重要視される領域の一つである。本研究成果は、Kv1.5チャネルが尿酸結晶によるマクロファージでのNLRP3インフラマソーム活性化し、その分泌成分が心房筋でのNLRP3インフラマソームを活性化および電気的リモデリングを引き起こし、心房細動発生に寄与することを明らかにした。Kv1.5チャネルは高尿酸血症による痛風および心房細動の治療標的なり得ると考えている。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (26 results)

All 2022 2021 2020 2019 2018

All Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 11 results) Presentation (13 results) (of which Invited: 1 results)

  • [Journal Article] Xanthinuria Type 1 with a Novel Mutation in Xanthine Dehydrogenase and a Normal Endothelial Function2022

    • Author(s)
      Satoshi Miyazaki, hisatome I, et al
    • Journal Title

      Internal Medicine

      Volume: 61 Issue: 9 Pages: 1383-1386

    • DOI

      10.2169/internalmedicine.7897-21

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2022-05-01
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thrombin induces a temporal biphasic vascular response through the differential phosphorylation of endothelial nitric oxide synthase via protease-activated receptor-1 and protein kinase C2022

    • Author(s)
      Akihiro Okamura, Hisatome I, et al
    • Journal Title

      Journal of pharmacological sciences

      Volume: 48 Issue: 4 Pages: 351-357

    • DOI

      10.1016/j.jphs.2022.02.001

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early effects of an adipose-derived stem cell sheet against detrusor underactivity in a rat cryo-injury model2022

    • Author(s)
      Shogo Teraoka, Masashi Honda, Karen Makishima, Ryutaro Shimizu , Panagiota Tsounapi, Tetsuya Yumioka, Hideto Iwamoto, Peili Li , et al
    • Journal Title

      Life sciences

      Volume: online ahead of print Pages: 0-0

    • DOI

      10.1016/j.lfs.2022.120604

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kv1.5 channel mediates monosodium urate-induced activation of NLRP3 inflammasome in macrophages and arrhythmogenic effects of urate on cardiomyocytes2022

    • Author(s)
      Peili Li, Yasutaka Kurata, Fikri Taufiq, et al
    • Journal Title

      Molecular Biology Reports

      Volume: online ahead of print Issue: 7 Pages: 0-0

    • DOI

      10.1007/s11033-022-07378-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] α1-Adrenergic receptor mediates adipose-derived stem cell sheet-induced protection against chronic heart failure after myocardial infarction in rats2022

    • Author(s)
      Horie H, Hisatome I, Kurata Y, Yamamoto Y, Notsu T, Adachi M, Li P, et al
    • Journal Title

      Hypertension research

      Volume: 45 Issue: 2 Pages: 283-291

    • DOI

      10.1038/s41440-021-00802-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Uric Acid as a Risk Factor for Chronic Kidney Disease and Cardiovascular Disease ― Japanese Guideline on the Management of Asymptomatic Hyperuricemia ―2021

    • Author(s)
      Hisatome Ichiro、Li Peili、Miake Junichiro、Taufiq Fikri、Mahati Endang、Maharani Nani、Utami Sulistiyati Bayu、Kuwabara Masanari、Bahrudin Udin、Ninomiya Haruaki
    • Journal Title

      Circulation Journal

      Volume: 85 Issue: 2 Pages: 130-138

    • DOI

      10.1253/circj.CJ-20-0406

    • NAID

      130007975319

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2021-01-25
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages2020

    • Author(s)
      Taufiq F, Li P, Kuwabara M, et al
    • Journal Title

      Vascular Failure

      Volume: 3 Issue: 2 Pages: 59-67

    • DOI

      10.30548/vascfail.3.2_59

    • NAID

      130007835261

    • ISSN
      2432-4477
    • Year and Date
      2020-04-24
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evidence for Urate Uptake Through Monocarboxylate Transporter 9 Expressed in Mammalian Cells and Its Enhancement by Heat Shock2020

    • Author(s)
      Otani Naoyuki、Kurata Yasutaka、Maharani Nani、Kuwabara Masanari、Ikeda Nobuhito、Notsu Tomomi、Li Peili、Miake Junichiro、Yoshida Akio、Sakaguchi Hiromi、Higaki Katsumi、Nakasone Naoe、Tsuneto Motokazu、Shirayoshi Yasuaki、Ouchi Motoshi、Ninomiya Haruaki、Yamamoto Kazuhiro、Anzai Naohiko、Hisatome Ichiro
    • Journal Title

      Circulation Reports

      Volume: 2 Issue: 8 Pages: 425-432

    • DOI

      10.1253/circrep.cr-20-0016

    • NAID

      130007885744

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hyperuricemia as a Risk Factor for Atrial Fibrillation Due to Soluble and Crystalized Uric Acid2019

    • Author(s)
      Fikri Taufiq, Peili Li*; Junichiro Miake, Ichiro Hisatome,
    • Journal Title

      Circulation Reports

      Volume: 1 Issue: 11 Pages: 469-473

    • DOI

      10.1253/circrep.CR-19-0088

    • NAID

      130007742752

    • ISSN
      2434-0790
    • Year and Date
      2019-11-08
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Uric Acid-Induced Enhancements of Kv1.5 Protein Expression and Channel Activity via the Akt-HSF1-Hsp70 Pathway in HL-1 Atrial Myocytes2019

    • Author(s)
      Taufiq Fikri、Maharani Nani、Li Peili、Kurata Yasutaka、Ikeda Nobuhito、Kuwabara Masanari、Otani Naoyuki、Miake Junichiro、Hasegawa Akira、Tsuneto Motokazu、Shirayoshi Yasuaki、Ninomiya Haruaki、Saitoh Tatsuya、Nakai Akira、Yamamoto Kazuhiro、Hisatome Ichiro
    • Journal Title

      Circulation Journal

      Volume: 83 Issue: 4 Pages: 718-726

    • DOI

      10.1253/circj.CJ-18-1088

    • NAID

      130007620506

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2019-03-25
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibitory effects of class I antiarrhythmic agents on Na+ and Ca2+ currents of human iPS cell-derived cardiomyocytes.2019

    • Author(s)
      Yonemizu S, Masuda K, Kurata Y, Notsu T, Higashi Y, Fukumura K, Li P, Ninomiya H, Miake J, Tsuneto M, Shirayoshi Y, Hisatome I.
    • Journal Title

      Regen Ther.

      Volume: 10 Pages: 104-111

    • DOI

      10.1016/j.reth.2018.12.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages2019

    • Author(s)
      Fikri Taufiq, Peili Li, Masanari Kuwabara, Yasutaka Kurata, et al
    • Journal Title

      Vascular Failure

      Volume: 3 Pages: 59-67

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Restoration of mutant hERG stability by inhibition of HDAC62018

    • Author(s)
      Li Peili、Kurata Yasutaka、Endang Mahati、Ninomiya Haruaki、Higaki Katsumi、Taufiq Fikri、Morikawa Kumi、Shirayoshi Yasuaki、Horie Minoru、Hisatome Ichiro
    • Journal Title

      J mol Cell cardiol

      Volume: 115 Pages: 158-169

    • DOI

      10.1016/j.yjmcc.2018.01.009

    • NAID

      120007170666

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Activation of NLRP3 inflammasome in mouse cardiomyocyte HL-1 by monosodium urate crystal-stimulated macrophages2022

    • Author(s)
      李 佩俐
    • Organizer
      第55回日本痛風 尿酸核酸代謝学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Role of Kv1.5 in monosodium urate crystal-induced activation of NLRP3 inflammasome in mouse cardiomyocyte HL-12022

    • Author(s)
      Peili Li
    • Organizer
      第86回日本循環器学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] キサンチンオキシダーゼ阻害剤の有効性2022

    • Author(s)
      桑原政成 浜田紀宏 李佩俐
    • Organizer
      第55回日本痛風 尿酸核酸代謝学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Inhibition of Kv1.5 channels attenuates Monosodium Urate induced NLRP3 inflammasome activation in human macrophages2021

    • Author(s)
      Peili Li
    • Organizer
      第67回日本不整脈心電学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Monosodium urate crystal-induced NLRP3 inflammasome activation is regulated by Kv1.5 channel2020

    • Author(s)
      Li P, Taufiq F, 桑原政成, et al
    • Organizer
      第53回日本痛風尿酸核酸学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Effects of FYU981 on the urate crystal-induced activation of NLRP3 inflammasome in macrophage2020

    • Author(s)
      Taufiq F, Li P, 水田栄之助, et al
    • Organizer
      第53回日本痛風尿酸核酸学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Monosodium urate crystal-induced NLRP3 inflammasome activation is regulated by Kv1.5 channel2020

    • Author(s)
      Peili Li, Fikri Taufiq
    • Organizer
      第53回日本痛風尿酸核酸学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] HDAC6 regulates electrophysiological properties of HL-1 cells via ERG channel2019

    • Author(s)
      Peili Li, Yasutaka Kurata, Fikri Taufiq, Yasuaki Shirayoshi, Ichiro Hisatome
    • Organizer
      第83回日本循環器学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Uric Acid-induced Increases of protein and Channel Activity of Atrial Kv1.5 via Akt-HSF1-Hsp70 Axis2019

    • Author(s)
      Fikri Taufiq, Nani Maharani, Peili Li
    • Organizer
      第83回日本循環器学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Kv1.5 Channels regulate the NLRP3 Inflammasome activation in macrophages induced by monosodium Urate2019

    • Author(s)
      Peili Li, Yasutaka Kurata, Fikri Taufiq , Yasuaki Shirayoshi, Ichiro Hisatome
    • Organizer
      第66回日本不整脈心電学会学術大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Inhibition of HDAC 6 manipulates electrophysiological properties of HL-1 cells via regulation of ERG channel2018

    • Author(s)
      Peili Li, et al
    • Organizer
      第65回不整脈心電学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Inhibition of HDAC 6 manipulates electrophysiological properties of HL-1 cells2018

    • Author(s)
      Peili Li, et al
    • Organizer
      第二回日本循環器学会基礎研究フォーラム
    • Related Report
      2018 Research-status Report
  • [Presentation] Effects of class Ⅰantiarrhythmic agents on ionic currents of human iPS cell-derived ventricular myocytes2018

    • Author(s)
      Sayaka Yonemizu, Peili Li, et al
    • Organizer
      第65回不整脈心電学会学術大会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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