Analysis of molecular mechanism of FK506-induced endothelial dysfunction

• Project/Area Number: 24790985
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Hyogo Medical University
• Principal Investigator: EGUCHI Ryoji 兵庫医科大学, 医学部, 助教 (00461088)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 血管生物学 / 血管内皮細胞 / 血管内皮障害 / 免疫抑制剤 / 管腔崩壊 / 細胞死 / 3次元培養 / アポトーシス / FK506 / ERK1/2 / Akt / カスパーゼ / calcineurin / caspase

Outline of Final Research Achievements

FK506 has been used in hematopoietic stem cell transplantations to suppress immune function, but is associated with severe endothelial dysfunction. We investigated whether FK506 induces endothelial dysfunction using a three-dimensional culture blood vessel model, in which human umbilical vein endothelial cells form and maintain capillary-like tube and lumen structures. We found that FK506 induced tube breakdown and endothelial cell death through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway and that recombinant human soluble thrombomodulin suppresses FK506-induced endothelial cell death through prevention of Akt inactivation.

Research Products

• [Journal Article] Recombinant human soluble thrombomodulin attenuates FK506- induced endothelial dysfunction through prevention of Akt inactivation. (2014)
  • Author(s): Eguchi R, Fujimori Y, Okada M, Tamaki H, Wakabayashi I, Ogawa H.
  • Journal Title: Experimental Cell Research Volume: 323 Issue: 1 Pages: 112-117
  • DOI: 10.1016/j.yexcr.2014.02.023
  • Peer Reviewed
• [Journal Article] FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway. (2013)
  • Author(s): Eguchi R, Kubo S, Ohta T, Kunimasa K, Okada M, Tamaki H, Kaji K, Wakabayashi I, Fujimori Y, Ogawa H
  • Journal Title: Cellular Signalling Volume: 25 Issue: 9 Pages: 1731-1738
  • DOI: 10.1016/j.cellsig.2013.05.008
  • Peer Reviewed
• [Journal Article] Serum thioredoxin-1 as a diagnostic marker for malignant peritoneal mesothelioma. (2013)
  • Author(s): Tabata C, et al.
  • Journal Title: J Clin Gastroenterol Volume: 47 Issue: 1 Pages: e7-e11
  • DOI: 10.1097/mcg.0b013e31824e901b
  • Peer Reviewed
• [Journal Article] Different mechanisms causing loss of mismatched human leukocyte antigens in relapsing t(6;11)(q27;q23) acute myeloid leukemia after haploidentical transplantation. (2012)
  • Author(s): Tamaki H, Fujioka T, Ikegame K, Yoshihara S, Kaida K, Taniguchi K, Kato R, Tokugawa T, Nakata J, Inoue T, Yano A, Eguchi R, Okada M, Maruya E, Saji H, Ogawa H.
  • Journal Title: European Journal of Haematology Volume: 89 Issue: 6 Pages: 497-500
  • DOI: 10.1111/ejh.12017
  • Peer Reviewed
• [Presentation] 組換え型トロンボモジュリンはFK506が誘導するAktの不活性化により引き起こされる血管内皮障害を抑制する (2015)
  • Author(s): 江口良二、藤盛好啓、岡田昌也、玉置広哉、若林一郎、小川啓恭
  • Organizer: 第37回日本造血細胞移植学会
  • Place of Presentation: 神戸国際会議場・神戸ポートピアホテル
  • Year and Date: 2015-03-05 – 2015-03-07
  • Invited
• [Presentation] Recombinant human soluble thrombomodulin attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation (2014)
  • Author(s): 江口良二、藤盛好啓、小川啓恭、若林一郎
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] FK506はcalcineurin阻害やcaspase経路とは独立してAktとERK1/2活性の減衰により血管内皮障害を誘導する (2013)
  • Author(s): 江口良二、藤盛好啓、久保秀司、小川啓恭、若林一郎
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway. (2013)
  • Author(s): 江口良二、藤盛好啓、久保秀司、小川啓恭、若林一郎
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里阪急ホテル
• [Presentation] SFK inhibition overcomes resistance to anoikis and facilitates cisplatin-induced apoptosis in human mesothelioma cells. (2013)
  • Author(s): 江口良二、田端千春、小川啓恭、中野孝司、藤盛好啓
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Recombinant thrombomodulin suppresses FK506-induced endothelial death by preｖenting Akt inactivation. (2013)
  • Author(s): 江口良二、藤盛好啓、岡田昌也、若林一郎、小川啓恭
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市教育文化会館
• [Presentation] FK506 binding protein 12 is involved in FK506-induced endothelial dysfunction. (2012)
  • Author(s): 江口良二、藤盛好啓、久保秀司、小川啓恭
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 国立京都国際会館
• [Presentation] Recombinant thrombomodulin suppresses FK506-induced endothelial cell death. (2012)
  • Author(s): 江口良二、岡田昌也、藤盛好啓、相馬俊裕、小川啓恭
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 国立京都国際会館
• [Presentation] A complex of FK506 and FK506-binding protein 12 is involved in FK506-induced breakdown of capillary-like tube structures independently of calcineurin inhibition. (2012)
  • Author(s): 江口良二、藤盛好啓、久保秀司、小川啓恭
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡