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Development of methods of clinical experiment and biomarkers for the assessment of cardiovascular drugs

Research Project

Project/Area Number 19590541
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied pharmacology
Research InstitutionUniversity of the Ryukyus

Principal Investigator

UEDA Shinichiro  University of the Ryukyus, 大学院・医学研究科, 教授 (80285105)

Co-Investigator(Kenkyū-buntansha) 大屋 祐輔  琉球大学, 大学院・医学研究科, 准教授 (30240964)
安 隆則  琉球大学, 大学院・医学研究科, 准教授 (40265278)
浦田 秀則  福岡大学, 医学部, 教授 (30289524)
松岡 秀洋  久留米大学, 医学部, 准教授 (80248393)
山川 研  琉球大学, 大学院・医学研究科, 助教 (00363664)
Co-Investigator(Renkei-kenkyūsha) OHYA Yusuke  琉球大学, 大学院・医学研究科, 教授 (30240964)
YASU Takanori  琉球大学, 大学院・医学研究科, 准教授 (40265278)
URATA Hidenori  福岡大学, 筑紫病院, 教授 (30289524)
MATSUOKA Hidehiro  久留米大学, 医学部, 准教授 (80248393)
YAMAKAWA Ken  琉球大学, 大学院・医学研究科, 助教 (00363664)
Project Period (FY) 2007 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords心血管薬 / 薬効評価システム / サロゲートマーカー / レニンアンジオテンシン系 / ヒト内皮機能 / 代替エンドポイント / FMD / アディポネクチン / 血管内皮機能 / インスリン感受性
Research Abstract

1. We assessed methods of the measurement of endothelial function by flow-mediated vasodilatation and of aortic stiffness by pulse wave velocity. We also standardized the method of flow-mediated vasodilatation, which had varied among researchers.
2. We estimated the association of insulin sensitivity measured by glucose clamp technique and serum metabolic marker such as adiponectin.
3. The methods of experiments in humans for the assessment of effects of elevated free fatty acids on angiotensin II forming activity in leukocytes, endothelial function, insulin sensitivity, and leukocyte activation was established. We tested effects of several cardiovascular drugs in this lipid loading experiment mimicking visceral fat obesity. We found that elevated FFA caused endothelial dysfunction, microcirculatory dysfunction (leukocyte activation), insulin resistance partly via leukocyte renin-angiotensin system. This experimental protocol may be useful for the assessment of anti-atherosclerotic drugs. Leukocyte angiotensin II forming activity could be a biomarker for visceral fat obesity linking to vascular dysfunction.

Report

(4 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (40 results)

All 2010 2009 2008 2007 Other

All Journal Article (20 results) (of which Peer Reviewed: 8 results) Presentation (20 results)

  • [Journal Article] FFA causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells2010

    • Author(s)
      Azekoshi Y, Yasu T, Watanabe S, Tagawa T, Uehara Y, Abe S, Urata H, Yamakawa K, Momomura S, Ueda S
    • Journal Title

      Hypertension 56

      Pages: 136-142

    • Related Report
      2009 Final Research Report
  • [Journal Article] FFA causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells2010

    • Author(s)
      Azekoshi Y, et al
    • Journal Title

      Hypertension (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of pitavastatin on fasting and postprandial endothelial function and blood rheology in patients with stable coronary artery disease.2009

    • Author(s)
      Arao K, Yasu T, Umemoto T, JimboS, Ikeda N, Ueda S, Momomura S
    • Journal Title

      Circ J 73

      Pages: 1523-30

    • NAID

      10025934077

    • Related Report
      2009 Final Research Report
  • [Journal Article] Differentiation of endothelial progenitor cells A useful biomarker?2009

    • Author(s)
      Yasu T
    • Journal Title

      Circ J 73

      Pages: 1199-1200

    • NAID

      10025932239

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] プレチスモグラフによる血管内皮機能測定2009

    • Author(s)
      井上卓, 植田真一郎
    • Journal Title

      血栓と循環 17

      Pages: 58-62

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Vascular Failure Workshop Group. Flow-mediated vasodilation as a diagnostic modality for vascular failure.2008

    • Author(s)
      Inoue T, Matsuoka H, Higashi Y, Ueda S, Sata M, Shimada KE, Ishibashi Y, Node K
    • Journal Title

      Hypertens Res 31

      Pages: 2105-13

    • Related Report
      2009 Final Research Report
  • [Journal Article] Daily exercise and bone marrow-derived CD34+/133+ cells after myocardial infarction treated by bare metal stent implantation.2008

    • Author(s)
      Ikeda N, Yasu T, Kubo N, Nakamura T, Sugawara Y, Ueda S, Ishikawa SE, Saito M, Kawakami M, Momomura S
    • Journal Title

      Circ J 72

      Pages: 897-901

    • NAID

      110006783824

    • Related Report
      2009 Final Research Report
  • [Journal Article] Slower onset of vasodilating action of brain natriuretic peptide (BNP) compared to atrial natriuretic peptide (ANP) in human forearm resistant vessels.2008

    • Author(s)
      Minami H, Yasu T, Tagawa T, Yamakawa K, Ueda S
    • Journal Title

      Eur J Clin Pharmacol 64

      Pages: 859-62

    • Related Report
      2009 Final Research Report
  • [Journal Article] Comparability and reproducibility of the carotid-femoral pulse wave velocity measurements using a multi-element carotid tonometry sensor.2008

    • Author(s)
      Ueda I, Tagawa T, Watanabe S, Yamakawa K, Yasu T, Ueda S
    • Journal Title

      J Hum Hypertens 22

      Pages: 699-703

    • Related Report
      2009 Final Research Report
  • [Journal Article] Comparability and reproducibility of the carotid-femoral pulse wave velocity measurements using a multi-elment carotid tonometry sensor2008

    • Author(s)
      Ikuko Ueda
    • Journal Title

      Journal of Human Hypertension 22

      Pages: 699-703

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Slower onset of vasodilating action of brain natriuretic peptide (BNP) compared to atrial natriuretic peptide (ANP) in human forearm resistant vessels.2008

    • Author(s)
      Hironobu Minami
    • Journal Title

      Eur J Clin Pharmacol 64

      Pages: 859-862

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vascular lipotoxicity: endothelial dysfunction via fatty acid-induced reactive oxygen species pverproduction in obese Zucker diabetic rats2007

    • Author(s)
      Chinen I, Shimabukuro M, Yamakawa K, Ueda S, et. al
    • Journal Title

      Endocrinology 148

      Pages: 160-165

    • Related Report
      2009 Final Research Report
  • [Journal Article] A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects.2007

    • Author(s)
      Matsuhisa M, Yamasaki Y, Emoto M, Shimabukuro M, Ueda S, Funahashi T, Matsuzawa Y
    • Journal Title

      Diabetes Res Clin Pract 77

      Pages: 151-4

    • Related Report
      2009 Final Research Report
  • [Journal Article] Effects of dietary composition on postprandial endothelial function and adiponectin concentrations in healthy humans: a crossover controlled study.2007

    • Author(s)
      Shimabukuro M, Chinen I, Higa N, Takasu N, Yamakawa K, Ueda S
    • Journal Title

      Am J Clin Nutr 86

      Pages: 923-8

    • Related Report
      2009 Final Research Report
  • [Journal Article] 心血管サロゲートマーカーとしてのFMD測定と標準化案2007

    • Author(s)
      松岡秀洋、東幸仁、野出孝一、植田真一郎
    • Journal Title

      Jpn J Clin Pharmacol Ther 38

      Pages: 305-309

    • Related Report
      2009 Final Research Report
  • [Journal Article] サロゲートマーカーの必要性と限界2007

    • Author(s)
      植田真一郎
    • Journal Title

      Jpn J Clin Pharmacol Ther 38

      Pages: 295-298

    • NAID

      10019991823

    • Related Report
      2009 Final Research Report 2007 Annual Research Report
  • [Journal Article] 心血管サロゲートマーカーとしてのFMD測定とその標準化案(statement)2007

    • Author(s)
      松岡秀洋, 他
    • Journal Title

      Jpn J Clin Pharmacol Ther 38

      Pages: 305-309

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of dietary composition on postprandial endothelial function and adiponectin concentrations in healthy humans: a crossover controlled study.2007

    • Author(s)
      Shimabukuro M, et. al.
    • Journal Title

      Am J Clin Nutr 86

      Pages: 923-928

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects.2007

    • Author(s)
      Metsuhisa M
    • Journal Title

      Diabetes Res. Clin. Pract. 77

      Pages: 151-154

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparability and reproducibility of the carotid-femoral pulse wave velocity measurements using a multi-element carotid tonometry sensor.

    • Author(s)
      Ueda I, et. al.
    • Journal Title

      J Hum Hypertens (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] Elevated FFA from visceral adipose tissue cause microcirculatory dysfunction partly via local renin-angiotensin system in mononuclear cells.2010

    • Author(s)
      安隆則、小林真由美、植田真一郎
    • Organizer
      第73回日本循環器学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2010-03-21
    • Related Report
      2009 Final Research Report
  • [Presentation] メタボリックシンドロームにおけるkey playerとしてのFFA-レニンーアンジオテンシン系2010

    • Author(s)
      植田真一郎
    • Organizer
      第73回日本循環器学会学術集会シンポジウム
    • Place of Presentation
      大阪
    • Year and Date
      2010-03-20
    • Related Report
      2009 Final Research Report
  • [Presentation] 動脈硬化性疾患のバイオマーカー2009

    • Author(s)
      植田真一郎
    • Organizer
      第30回日本臨床薬理学会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2009-12-02
    • Related Report
      2009 Annual Research Report
  • [Presentation] Ca拮抗薬によるFFA惹起性内皮機能低下と白血球活性化の改善2009

    • Author(s)
      安隆則、小林真由美、山川研、植田真一郎
    • Organizer
      第31回日本高血圧学会総会
    • Place of Presentation
      札幌
    • Year and Date
      2009-10-11
    • Related Report
      2009 Final Research Report
  • [Presentation] アンジオテンシンII受容体拮抗薬はFFA惹起性インスリン抵抗性を改善する2009

    • Author(s)
      畔越陽子、小林真由美、安隆則、山川研、植田真一郎
    • Organizer
      第31回日本高血圧学会総会
    • Place of Presentation
      札幌
    • Year and Date
      2009-10-10
    • Related Report
      2009 Final Research Report
  • [Presentation] Elevated FFAs From Visceral Adipose Tissue Cause Microcirculatory Dysfunction Partly via Local Renin-Angiotensin System in Mononuclear Cells2009

    • Author(s)
      安隆則
    • Organizer
      American Collage of Cardiology
    • Place of Presentation
      オーランド(米国)
    • Year and Date
      2009-03-29
    • Related Report
      2008 Annual Research Report
  • [Presentation] Elevated FFA from visceral adipose tissue cause microcirculatory dysfunction partly via local renin-angiotensin system in mononuclear cells.2009

    • Author(s)
      Yasu T, Azekoshi Y, Yamakawa K, Urata H, Ueda S
    • Organizer
      American Collage of Cardiology
    • Place of Presentation
      Orland, USA
    • Year and Date
      2009-03-27
    • Related Report
      2009 Final Research Report
  • [Presentation] Elevated FFAs From Visceral Adipose Tissue Cause Microcirculatory Dysfunction Partly via Local Renin-Angiotensin System in Mononuclear Cells2009

    • Author(s)
      安隆則
    • Organizer
      第73回日本循環器学会
    • Place of Presentation
      大阪市(大阪府)大阪国際会議場
    • Year and Date
      2009-03-22
    • Related Report
      2008 Annual Research Report
  • [Presentation] Enhanced Angiotensin II Forming Activity In Mononuclear Cell By Elevated FFAs : Possible Implication in Endothelial Dysfunction as Mobile Renin-Angiotensin System2008

    • Author(s)
      植田真一郎
    • Organizer
      American Heart Association
    • Place of Presentation
      ニューオリンズ(米国)
    • Year and Date
      2008-11-13
    • Related Report
      2008 Annual Research Report
  • [Presentation] Angiotensin II production in human mononuclear cells is enhanced by elevated FFA.2008

    • Author(s)
      Ueda S, Azekoshi Y, Yasu T, Yamakawa K, Urata H
    • Organizer
      Possible implication in endothelial dysfunction as mobile renin-angiotensin system. Scientific Session of American Heart Association
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2008-11-10
    • Related Report
      2009 Final Research Report
  • [Presentation] 安隆則内因性、外因性のアンジオテンシン負荷はヒト血管内皮機能を低下させない2008

    • Author(s)
      植田真一郎、渡部彩子、田川辰也
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄
    • Year and Date
      2008-10-27
    • Related Report
      2009 Final Research Report
  • [Presentation] FFA負荷は単核球のアンジオテンシンII産生能を亢進させる2008

    • Author(s)
      畔越陽子、植田真一郎、浦田秀則、安隆則
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄
    • Year and Date
      2008-10-25
    • Related Report
      2009 Final Research Report
  • [Presentation] メタボリックシンドロームにおけるインスリン感受性と血管内皮機能の関連2008

    • Author(s)
      山川研、島袋充生、田川辰也、植田真一郎
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄
    • Year and Date
      2008-10-25
    • Related Report
      2009 Final Research Report
  • [Presentation] アンジオテンシンII受容体拮抗薬はFFA惹起性インスリン抵抗性を改善する。2008

    • Author(s)
      畔越陽子
    • Organizer
      第31回日本高血圧学会
    • Place of Presentation
      札幌市(北海道)ロイトン札幌
    • Year and Date
      2008-10-10
    • Related Report
      2008 Annual Research Report
  • [Presentation] Ca拮抗薬によるFFA惹起性血管内皮機能低下と白血球活性化の改善2008

    • Author(s)
      安隆則
    • Organizer
      第31回日本高血圧学会
    • Place of Presentation
      札幌市(北海道)ロイトン札幌
    • Year and Date
      2008-10-10
    • Related Report
      2008 Annual Research Report
  • [Presentation] メタボリック症候群における血管内皮機能とインスリン感受性の関連2007

    • Author(s)
      山川 研, 他
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄県
    • Year and Date
      2007-10-25
    • Related Report
      2007 Annual Research Report
  • [Presentation] 外因性、内因性アンジオテンシンII負荷はヒト血管内皮機能を悪化させない2007

    • Author(s)
      渡部彩子, 他
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄県
    • Year and Date
      2007-10-25
    • Related Report
      2007 Annual Research Report
  • [Presentation] FFA負荷は単核球のアンジオテンシンII産生能を亢進させる2007

    • Author(s)
      畔越陽子, 他
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄県
    • Year and Date
      2007-10-24
    • Related Report
      2007 Annual Research Report
  • [Presentation] 降圧利尿薬臨床試験(DIME試験)の研究支援体制2007

    • Author(s)
      植田育子, 他
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄県
    • Year and Date
      2007-10-24
    • Related Report
      2007 Annual Research Report
  • [Presentation] 血管内皮機能 若手研究者のための教育セッション2007

    • Author(s)
      植田真一郎
    • Organizer
      第30回日本高血圧学会総会
    • Place of Presentation
      沖縄県
    • Year and Date
      2007-10-24
    • Related Report
      2007 Annual Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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