Mechanism of the intimal thickening formation of ductus arteriosus focused on tissue-type plasminogen activator

• Project/Area Number: 16H07107
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Yokohama City University
• Principal Investigator: Saito Junichi 横浜市立大学, 医学部, 助教 (30779301)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 動脈管 / 内膜肥厚 / 内弾性板 / 組織型プラスミノーゲン活性化因子 / プラスミノーゲン / マトリックスメタロプロテアーゼ / マトリックスメタロプロテイナーゼ / 循環器 / 小児 / 新生児

Outline of Final Research Achievements

In addition to smooth muscle contraction, the ductal tissue remodeling, such as intimal thickening (IT) formation, is necessary for complete anatomical closure of the ductus arteriosus (DA). Although disruption of the internal elastic lamina (IEL) is the early process of the DA remodeling, the molecular mechanisms have not been fully investigated. This study revealed that tissue-type plasminogen activator (t-PA) was highly expressed in the endothelial cells of the DA and that it promoted the plasmin-induced activation of matrix metalloproteinase and the subsequent disruption of the IEL, which may contribute to IT formation in the DA. In human preterm infants, serum plasminogen levels are physiologically lower than those in adults. Plasminogen supplementation may promote the IT formation and subsequent closure of the DA.

Research Products

• [Journal Article] Tissue-type plasminogen activator contributes to remodeling of the rat ductus arteriosus. (2018)
  • Author(s): Saito J, Yokoyama U, Nicho N, Zheng YW, Ichikawa Y, Ito S, Umemura M, Fujita T, Ito S, Taniguchi H, Asou T, Masuda M, Ishikawa Y.
  • Journal Title: PLoS One Volume: 13(1) Issue: 1 Pages: e0190871-e0190871
  • DOI: 10.1371/journal.pone.0190871
  • Peer Reviewed / Open Access
• [Journal Article] Attenuation of ductus arteriosus intimal thickening in preterm sheep twins compared with singletons (2017)
  • Author(s): Ito Satoko、Yokoyama Utako、Saito Junichi、Sato Shinichi、Usuda Haruo、Watanabe Shimpei、Kitanishi Ryuta、Miura Yuichiro、Saito Masatoshi、Hanita Takushi、Matsuda Tadashi、Ishikawa Yoshihiro
  • Journal Title: The Journal of Physiological Sciences Volume: 67 Issue: 6 Pages: 723-729
  • DOI: 10.1007/s12576-017-0565-5
  • NAID: 40021363517
  • Peer Reviewed / Open Access
• [Presentation] Tissue-type plasminogen activator promotes intimal thickening formation of the ductus arteriosus (2018)
  • Author(s): Junichi Saito, Utako Yokoyama, Naoki Nicho, Yun-Wen Zheng, Satoko Ito, Shuichi Ito, Hideki Taniguchi, Toshihide Asou, Munetaka Masuda, Yoshihiro Ishikawa
  • Organizer: Weinstein 2018
  • Int'l Joint Research
• [Presentation] 組織型プラスミノーゲン活性化因子による動脈管のリモデリング (2018)
  • Author(s): 齋藤純一, 横山詩子, 石川義弘
  • Organizer: 第95回日本生理学会大会
• [Presentation] ヒト動脈管の遺伝子解析により明らかとなった組織型プラスミノーゲン活性化因子による動脈管内弾性板の分解 (2017)
  • Author(s): 齋藤純一、横山詩子、石川義弘
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松(静岡県浜松市)
  • Year and Date: 2017-03-28
• [Presentation] ヒト動脈管の遺伝子解析により明らかとなった、組織型プラスミノーゲン活性化因子による動脈管内弾性板の分解 (2017)
  • Author(s): 齋藤純一, 横山詩子, 石川義弘
  • Organizer: 第94回日本生理学会大会
• [Presentation] Human Gene Profiling Reveals Connection of Tissue Plasminogen Activator to Intimal Thickening of the Ductus Arteriosus (2016)
  • Author(s): Junichi Saito, Utako Yokoyama, Munetaka Masuda, Toshihide Asou, Yoshihiro ishikawa
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-11