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

• Project/Area Number: 23592052
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: Tohoku 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: ¥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.

Research Products

• [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
  • 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
  • Peer Reviewed
• [Presentation] Activation of NRF2 Attenuates Hypoxia-induced Cardiopulmonary Alterations in Mice (2012)
  • 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
• [Presentation] Activation Of Nrf2 Attenuates Hypoxia-Induced Cardiopulmonary Alterations In Mice (2012)
  • 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
• [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
  • 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
• [Presentation] Activation Of Nrf2 Attenuates Hypoxia-Induced Cardiopulmonary Alterations In Mice (2012)
  • 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.
• [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.
• [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
  • 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
• [Presentation] An Nrf2 Activator, Oltipraz Attenuates Chronic Hypoxia-induced Cardiopulmonary Alterations in Mice (2011)
  • 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
• [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
• [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
• [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