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Therapeutic potency of Nrf2, a key antioxidative transcription factor, for pulmonary hypertension

Research Project

Project/Area Number 23592052
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Thoracic surgery
Research InstitutionTohoku University

Principal Investigator

HOSHIKAWA Yasushi  東北大学, 加齢医学研究所, 助教 (90333814)

Co-Investigator(Kenkyū-buntansha) KONDO Takashi  東北大学, 加齢医学研究所, 教授 (10195901)
FUKUMOTO Yoshihiro  久留米大学, 医学部, 教授 (70363372)
NODA Masafumi  東北大学, 大学病院, 講師 (70400356)
OKADA Yoshinori  東北大学, 加齢医学研究所, 准教授 (90323104)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords肺高血圧症 / 酸化ストレス / Nrf2 / 遺伝子改変マウス / 低酸素曝露 / 慢性呼吸器疾患 / 低酸素 / 肺高血圧 / 肺血管リモデリング / tenascin-C / 右心室肥大 / CD31陽性 / 活性化剤
Research Abstract

Three weeks of hypoxia exacerbated pulmonary hypertension (PH), right ventricular hypertrophy (RVH), and pulmonary vascular remodeling in mice. These pathological changes were associated with aberrant accumulation of a extracellular glycoprotein, Tenascin-C. Both administration of oltipraz, a potent Nrf2 activator, and Keap1 (negative regulator of Nrf2) knockdown significantly attenuated RVH and pulmonary vascular remodeling and concomitantly ameliorated Tenascin-C accumulation in the hypoxic mouse lungs. Expression of the Nrf2-regulated antioxidant enzymes was decreased in a patient with chronic obstructive pulmonary disease associated with PH. The decreased antioxidant enzymes may underlie the pathogenesis of cardiopulmonary changes in the patient with chronic obstructive pulmonary disease and PH. The efficacy of oltipraz highlights a promising therapeutic potency of Nrf2 activators for the prevention of PH in patients with hypoxemic lung disease.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (14 results)

All 2013 2012 2011 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (12 results) (of which Invited: 2 results)

  • [Journal Article] The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice.2013

    • Author(s)
      Eba S, Hoshikawa Y, Moriguchi T, Mitsuishi Y, Satoh H, Ishida K, Watanabe T, Shimizu T, Shimokawa H, Okada Y, Yamamoto M, Kondo T
    • Journal Title

      Am J Respir Cell Mol Biol

      Volume: 49(2 Issue: 2 Pages: 324-333

    • DOI

      10.1165/rcmb.2011-0396oc

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] The Nrf2 Activator Oltipraz Attenuates Chronic Hypoxia-Induced Cardiopulmonary Alterations In Mice.2013

    • Author(s)
      Eba S, Hoshikawa Y, Moriguchi T, Mitsuishi Y, Satoh H, Ishida K, Watanabe T, Shimizu T, Shimokawa H, Okada Y, Yamamoto M, Kondo T
    • Journal Title

      Am J Respir Cell Mol Biol.

      Volume: in press

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Activation of NRF2 Attenuates Hypoxia-induced Cardiopulmonary Alterations in Mice2012

    • Author(s)
      S. Eba, Y. Hoshikawa, T. Moriguchi, Y. Mitsuishi, H. Sato, K. Ishida, T. Watanabe, Y. Okada, M. Yamamoto, T. Kondo
    • Organizer
      Aspen Lung Conference
    • Place of Presentation
      Aspen, CO, USA.
    • Year and Date
      2012-06-07
    • Related Report
      2013 Final Research Report
  • [Presentation] Activation Of Nrf2 Attenuates Hypoxia-Induced Cardiopulmonary Alterations In Mice2012

    • Author(s)
      S. Eba, Y. Hoshikawa, T. Moriguchi, Y. Mitsuishi, H. Sato, T. Watanabe, Y. Watanabe, Y. Okada, T. Kondo
    • Organizer
      American Thoracic Society International Conference 2012
    • Place of Presentation
      San Francisco, CA, USA
    • Year and Date
      2012-05-20
    • Related Report
      2013 Final Research Report
  • [Presentation] 低酸素性肺高血圧症の病態解明の進歩2012

    • Author(s)
      星川康、江場俊介、森口尚、光石陽一郎、佐藤大希、石田和之、渡邊龍秋、岡田克典、近藤丘
    • Organizer
      第52回日本呼吸器学会学術講演会
    • Place of Presentation
      神戸
    • Year and Date
      2012-04-20
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] 肺高血圧病態における抗酸化ストレス転写因子Nrf2の役割の検討2012

    • Author(s)
      江場俊介,星川康光,石陽一郎,渡邊龍秋,川村昌輝,石橋直也,渡辺有為,野津田泰嗣,鈴木隆哉,大石久,前田寿美子,野田雅史顕,岡田克典,佐渡哲,桜田晃,遠藤千,山本雅之,近藤丘
    • Organizer
      White Conference 2012
    • Place of Presentation
      軽井沢
    • Year and Date
      2012-01-21
    • Related Report
      2013 Final Research Report
  • [Presentation] Activation Of Nrf2 Attenuates Hypoxia-Induced Cardiopulmonary Alterations In Mice2012

    • Author(s)
      S. Eba, Y. Hoshikawa, T. Moriguchi, Y. Mitsuishi, H. Sato, T. Watanabe, Y. Watanabe, Y. Okada, T. Kondo
    • Organizer
      2012 American Thoracic Society International Conference
    • Place of Presentation
      San Francisco, CA, U.S.A.
    • Related Report
      2012 Research-status Report
  • [Presentation] ACTIVATION OF NRF2 ATTENUATES HYPOXIA-INDUCED CARDIOPULMONARY ALTERATIONS IN MICE.2012

    • Author(s)
      S. Eba, Yasushi Hoshikawa*, T. Moriguchi, Y. Mitsuishi, H. Sato, K. Ishida, T. Watanabe, Y. Okada, M. Yamamoto, T. Kondo
    • Organizer
      Aspen Lung Conference
    • Place of Presentation
      Aspen, CO, U.S.A.
    • Related Report
      2012 Research-status Report
  • [Presentation] 低酸素性肺高血圧症の病態解明の進歩2012

    • Author(s)
      星川 康、江場俊介、森口 尚、光石陽一郎、佐藤大希、石田和之、渡邊龍秋、岡田克典、近藤 丘
    • Organizer
      第52回日本呼吸器学会学術講演会
    • Place of Presentation
      神戸コンベンションセンター
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Nrf2活性化剤oltiprazの長期低酸素曝露による心肺病変抑制効果2011

    • Author(s)
      江場俊介,星川康光,石陽一郎,渡邊龍秋,川村昌輝,石橋直也,渡辺有為,野津田泰嗣,鈴木隆哉,大石久,前田寿美子,野田雅史顕,岡田克典,佐渡哲,桜田晃,遠藤千,近藤丘
    • Organizer
      iPUC (integrated Pulmonary Circulation Research)-II
    • Place of Presentation
      東京
    • Year and Date
      2011-06-25
    • Related Report
      2013 Final Research Report
  • [Presentation] An Nrf2 Activator, Oltipraz Attenuates Chronic Hypoxia-induced Cardiopulmonary Alterations in Mice2011

    • Author(s)
      S Eba, Y Hoshikawa, Y Mitsuishi, H Sato, T Watanabe, Y Watanabe, S Maeda, Y Okada, T Kondo
    • Organizer
      American Thoracic Society International Conference 2011
    • Place of Presentation
      Denver, Colorado, USA
    • Year and Date
      2011-05-11
    • Related Report
      2013 Final Research Report
  • [Presentation] Nrf2活性化剤oltiprazの長期低酸素曝露による心肺病変抑制効果

    • Author(s)
      江場俊介 星川康 光石陽一郎 渡邊龍秋 川村昌輝 石橋直也 渡辺有為 野津田泰嗣 鈴木隆哉 大石久 前田寿美子 野田雅史 佐渡哲 桜田晃 遠藤千顕 岡田克典 近藤丘
    • Organizer
      iPUC (integrated Pulmonary Circulation Research)-II
    • Place of Presentation
      東京
    • Related Report
      2011 Research-status Report
  • [Presentation] An Nrf2 Activator, Oltipraz Attenuates Chronic Hypoxia-induced Cardiopulmonary Alterations in Mice

    • Author(s)
      S Eba, Y Hoshikawa, Y Mitsuishi, H Sato, T Watanabe, Y Watanabe, S Maeda, Y Okada, T Kondo
    • Organizer
      American Thoracic Society International Conference 2012
    • Place of Presentation
      Denver, Colorado, USA
    • Related Report
      2011 Research-status Report
  • [Presentation] 肺高血圧病態における抗酸化ストレス転写因子Nrf2の役割の検討

    • Author(s)
      江場俊介 星川康 光石陽一郎 渡邊龍秋 川村昌輝 石橋直也 渡辺有為 野津田泰嗣 鈴木隆哉 大石久 前田寿美子 野田雅史 佐渡哲 桜田晃 遠藤千顕 岡田克典 山本雅之 近藤丘
    • Organizer
      White Conference 2012
    • Place of Presentation
      軽井沢
    • Related Report
      2011 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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