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心血管系におけるペプチド分解酵素DPPIIIの生理学的・病理学的役割と分子機構

Research Project

Project/Area Number 17F17418
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field Pathological medical chemistry
Research InstitutionShiga University of Medical Science

Principal Investigator

扇田 久和  滋賀医科大学, 医学部, 教授 (50379236)

Co-Investigator(Kenkyū-buntansha) PANG XIAOLING  滋賀医科大学, 医学部, 外国人特別研究員
Project Period (FY) 2017-11-10 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2019: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2018: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2017: ¥400,000 (Direct Cost: ¥400,000)
Keywords糖尿病 / ペプチダーゼ / 心臓 / 腎臓 / ペプチド分解酵素 / 臓器保護効果 / 心血管疾患
Outline of Annual Research Achievements

ペプチド分解酵素の一つであるジペプチジルペプチダーゼIII(DPPIII)は、基質であるペプチド(およそ3~10残基の短いペプチド)をN末端から2残基ずつ分解するエキソペプチダーゼである。これまでの研究により、DPPIIIはアミノ酸8残基からなる昇圧ホルモンのアンジオテンシンIIを分解し、高血圧マウスにおいて降圧作用を有することを明らかにした。この研究成果を踏まえ、本研究では高血圧とは別に、心血管系に大きなダメージをもたらす生活習慣病の糖尿病、特に、糖尿病合併症の糖尿病腎症および糖尿病心筋症に着目して、これらの病態に対するDPPIIIの有効性とその機序について検討した。
糖尿病モデルdb/dbマウスにDPPIIIを週3回8週間連続して投与すると、腎障害の指標である尿中アルブミン排泄が有意に抑制された。免疫組織学的および電子顕微鏡による腎臓の解析では、糖尿病による腎糸球体の異常がDPPIII投与により著明に改善していた。一方、心筋を解析した結果では、心筋の線維化がDPPIII投与で減少していた。
DPPIIIによるこれらの臓器保護作用を検討するため、生食を投与したdb/dbマウス(コントロール)、DPPIIIを投与したdb/dbマウスそれぞれから血液を採取し、コントロールマウスで増加しているが、DPPIII投与マウスで減少しているペプチドをペプチドーム解析で網羅的に探索した。その結果、9アミノ酸からなるペプチド(ペプチドX)を見出した。実際に、ペプチドXはDPPIIIで速やかに切断され、また、ペプチドXをdb/dbマウスに投与すると腎臓、心臓の機能障害がさらに促進された。このことから、DPPIIIによる糖尿病合併症に対する抑制機序の一つとして、糖尿病で増加するペプチドXを分解していることが分かった。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (39 results)

All 2020 2019 2018 2017 Other

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 11 results) Presentation (25 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis2020

    • Author(s)
      Matsushima Shoko、Shimizu Akio、Kondo Manami、Asano Hirotsugu、Ueno Nobuhiro、Nakayama Hironao、Sato Naoko、Komeno Masahiro、Ogita Hisakazu、Kurokawa-Seo Misuzu
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 188-188

    • DOI

      10.1038/s41598-019-57040-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome.2020

    • Author(s)
      Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
    • Journal Title

      FASEB Journal

      Volume: 34 Issue: 5 Pages: 6399-6417

    • DOI

      10.1096/fj.201902991r

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019

    • Author(s)
      Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
    • Journal Title

      Circulation

      Volume: In press Issue: 18 Pages: 2157-2169

    • DOI

      10.1161/circulationaha.118.036761

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Pivotal Roles of the Epithelial Membrane Protein Family in Cancer Invasiveness and Metastasis2019

    • Author(s)
      Ahmat Amin MKB, Shimizu A, Ogita H.
    • Journal Title

      Cancers

      Volume: 11 Issue: 11 Pages: 1620-1620

    • DOI

      10.3390/cancers11111620

    • NAID

      120006766857

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy.2018

    • Author(s)
      Katagiri S, Iwasa M, Hayashi T, Hosono K, Yamashita T, Kuniyoshi K, Ueno S, Kondo M, Ueyama H, Ogita H, Shichida Y, Inagaki H, Kurahashi H, Kondo H, Ohji M, Hotta Y, Nakano T.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 11507-11507

    • DOI

      10.1038/s41598-018-29891-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac12018

    • Author(s)
      Ahmat Amin MKB, Shimizu A, Zankov DP, Sato A, Kurita S, Ito M, Maeda T, Yoshida T, Sakaue T, Higashiyama S, Kawauchi A, Ogita H.
    • Journal Title

      Oncogene

      Volume: 37 Issue: 40 Pages: 5416-5434

    • DOI

      10.1038/s41388-018-0286-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma2018

    • Author(s)
      Ogura S, Yoshida Y, Kurahashi T, Egawa M, Furuta K, Kiso S, Kamada Y, Hikita H, Eguchi H, Ogita H, Doki Y, Mori M, Tatsumi T, Takehara T.
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 30 Pages: 21022-21035

    • DOI

      10.18632/oncotarget.24781

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap2018

    • Author(s)
      Shimizu A, Zankov DP, Kurokawa-Seo M, Ogita H.
    • Journal Title

      Int J Mol Sci

      Volume: 19 Issue: 4 Pages: 1203-1203

    • DOI

      10.3390/ijms19041203

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Critical role of dipeptidyl peptidase III in cleavage of angiotensin II and its clinical implication2017

    • Author(s)
      清水昭男、扇田久和
    • Journal Title

      生化学

      Volume: 89 Issue: 3 Pages: 449-452

    • DOI

      10.14952/SEIKAGAKU.2017.890449

    • ISSN
      0037-1017
    • Year and Date
      2017-06-25
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential Effects of Myocardial Afadin on Pressure Overload-Induced Compensated Cardiac Hypertrophy2017

    • Author(s)
      Zankov, D.P., Sato, A., Shimizu, A., and Ogita, H.
    • Journal Title

      Circulation Journal

      Volume: 81 Issue: 12 Pages: 1862-1870

    • DOI

      10.1253/circj.CJ-17-0394

    • NAID

      130006219260

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathophysiological implications of dipeptidyl peptidases.2017

    • Author(s)
      Sato A, Ogita H.
    • Journal Title

      Curr Protein Pept Sci

      Volume: - Issue: 8 Pages: 843-849

    • DOI

      10.2174/1389203718666170329104936

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] ブルガダ症候群発症家系で見出された新たなTMEM168遺伝子変異の作用機序2020

    • Author(s)
      扇田久和
    • Organizer
      先端モデル動物支援プラットフォーム成果発表会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ジペプチジルペプチダーゼ-3が糖尿病での腎機能悪化を抑制2019

    • Author(s)
      大東親生、清水昭男、Xiaoling Pang、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Dipeptidyl peptidase III によるII型糖尿病モデルマウスの心・腎臓機能低下抑制効果2019

    • Author(s)
      米野雅大、清水昭男、Xiaoling Pang、扇田久和
    • Organizer
      先端モデル動物支援プラットフォーム若手支援技術講習会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Epithelial membrane protein 1はRac1を活性化してがん細胞の遊走を促進させがんの浸潤・転移を促進する2019

    • Author(s)
      清水昭男、Mohammad Khusni Bin Ahmat Amin、佐藤朗、扇田久和
    • Organizer
      日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Novel TMEM168 gene mutation in Brugada syndrome impairs sodium channel function via the Nav1.5 degradation.2019

    • Author(s)
      扇田久和、Dimitar P. Zankov、清水昭男
    • Organizer
      American Heart Association
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ジペプチジルペプチダーゼ-3が糖尿病での心腎機能悪化を抑制2019

    • Author(s)
      清水昭男、Xiaoling Pang、扇田久和
    • Organizer
      日本血管生物医学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 冠動脈周囲脂肪組織が動脈硬化に及ぼす影響2019

    • Author(s)
      鈴木友彰、扇田久和、佐藤朗、木下武、高島範之、近藤康生、宮下史寛、鉢呂康平、脇坂穂高
    • Organizer
      日本冠疾患学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] A novel TMEM168 gene mutation in familial Brugada syndrome attenuates Na+ channel function by modulating Nav1.5 expression.2019

    • Author(s)
      Dimitar P. Zankov、扇田久和
    • Organizer
      日本循環器学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Brugada syndrome-associated novel TMEM168 gene mutation attenuates Na+ channel function through Nav1.5 degradation.2019

    • Author(s)
      Dimitar P. Zankov、扇田久和
    • Organizer
      先端モデル動物支援プラットフォーム成果発表会
    • Related Report
      2018 Annual Research Report
  • [Presentation] VEGF-A/ニューロピリン1のシグナル伝達を阻害する細胞透過性ペプチドはがん細胞の浸潤と転移を抑制する2018

    • Author(s)
      瀬尾美鈴、吉田亜佑美、上野信洋、パラシカー・ガルギ、早田優香、太田成美、永安良多、栃尾凌太、福光一生、中西聖磨、米倉寛人、山 口淳史、浅野弘嗣、門之園哲哉、近藤科江、扇田久和、清水 昭男
    • Organizer
      日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Cardio- and reno-protective effect of dipeptidyl peptidase III.2018

    • Author(s)
      扇田久和、Xiaoling Pang、清水昭男
    • Organizer
      American Heart Association Scientific Sessions
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] EMP1 signaling promotes cancer invasiveness and metastasis.2018

    • Author(s)
      Mohammad Khusni Bin Ahmat Amin、清水昭男、Dimitar P. Zankov、佐藤朗、扇田久和
    • Organizer
      日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Novel therapeutic role for dipeptidyl peptidase III in the treatment of diabetic nephropathy.2018

    • Author(s)
      Xiaoling Pang、清水昭男、Dimitar P. Zankov、佐藤朗、石田哲夫、扇田久和
    • Organizer
      日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新たな遺伝子変異が病因と考えられた日本人青錐体1色覚(BCM)の症例2018

    • Author(s)
      岩佐真紀、上山久雄、片桐聡、林孝彰、山下高廣、七田芳則、大路正人、扇田久和
    • Organizer
      日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Protective role of intercalated disk protein afadin in the pressure-overloaded heart.2018

    • Author(s)
      扇田久和
    • Organizer
      日本循環器学会基礎研究フォーラム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Identification and arrhythmogenic significance of a novel TMEM168 mutation in Brugada syndrome.2018

    • Author(s)
      Dimitar P. Zankov、扇田久和
    • Organizer
      日本循環器学会基礎研究フォーラム
    • Related Report
      2018 Annual Research Report
  • [Presentation] 糖尿病性腎症に対するジペプチジルペプチダーゼIIIの保護作用2018

    • Author(s)
      山口侑汰、清水昭男、Xiaoling Pang、Dimitar P. Zankov、石田哲夫、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Critical role of intercalated disk protein afadin in cardiac protection against chronic pressure overload-induced heart failure.2018

    • Author(s)
      扇田久和
    • Organizer
      日本循環器学会(シンポジウム)
    • Related Report
      2017 Annual Research Report
  • [Presentation] Intercalated disk protein afadin prevents pressure overload-induced cardiac dysfunction in a stimulus-dependent manner.2018

    • Author(s)
      Dimitar P. Zankov、扇田久和
    • Organizer
      日本循環器学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Exome-wide analysis links nuclear membrane protein TMEM168 to the arrhythmogenesis in a family with inherited Brugada syndrome.2018

    • Author(s)
      Dimitar P. Zankov、扇田久和
    • Organizer
      先端モデル動物支援プラットフォーム成果発表会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Essential role of myocardial afadin in cardiac protecting during chronic pressure overload.2018

    • Author(s)
      Dimitar P. Zankov、扇田久和
    • Organizer
      日本循環器学会基礎研究フォーラム
    • Related Report
      2017 Annual Research Report
  • [Presentation] Deciphering signaling pathway of a novel cancer pro-invasive and -metastatic molecule, epithelial membrane protein 1.2017

    • Author(s)
      Mohammad Khusni B. Ahamad Amin、清水昭男、Dimitar P. Zankov、佐藤朗、扇田久和
    • Organizer
      生命科学系学会合同年次集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Myocardial afadin is essential for maintaining cardiac function against mechanical stress-induced, but not pharmacological stimulation-mediated, pressure overload.2017

    • Author(s)
      Hisakazu Ogita, Dimitar P. Zankov
    • Organizer
      American Heart Association
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Critical role of myocardial afadin in cardiac protection during chronic mechanical overload.2017

    • Author(s)
      Dimitar P. Zankov、清水昭男、佐藤朗、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ペプチド分解酵素DPP IIIの降圧作用と新規高血圧治療としての有用性2017

    • Author(s)
      扇田久和
    • Organizer
      臨床高血圧フォーラム(シンポジウム)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Remarks] 滋賀医科大学・分子病態生化学部門

    • URL

      http://www.shiga-med.ac.jp/~hqbioch2/

    • Related Report
      2019 Annual Research Report 2017 Annual Research Report
  • [Remarks] 滋賀医科大学分子病態生化学

    • URL

      http://www.shiga-med.ac.jp/~hqbioch2/

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 心不全非ヒト霊長類モデル動物の製造方法2019

    • Inventor(s)
      扇田久和、佐藤朗
    • Industrial Property Rights Holder
      扇田久和、佐藤朗
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-125286
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report

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Published: 2017-11-13   Modified: 2024-03-26  

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