A new function of glutathione as a warning signal in the heart

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08038
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Keio University
• Principal Investigator: KATSUMATA YOSHINORI 慶應義塾大学, 医学部(信濃町), 講師 (80464832)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: グルタチオン / 虚血再灌流 / フェロトーシス / 脂質酸化 / MRP1

Outline of Final Research Achievements

We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. The extracellular glutathione release during IR was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly multidrug resistance protein 1 (MRP1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple ox-PCs were significantly elevated in the ischemic region 12 h after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of ox-PCs. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury.

Free Research Field

循環器

Academic Significance and Societal Importance of the Research Achievements

心臓という代謝産物の分解が急速に進む臓器における正確な代謝の状態の空間的かつ時間的把握を確立するために、マイクロ波によるサンプル処理やマイクロダイアリシス法の開発を進めてきた。高分解能質量分析を組み合わせることで、虚血再灌流という、代謝変化が瞬時に代わる病態における代謝を正確に評価することができ、そのメカニズムの解明を進めることができた。特に、これまで不明であった、虚血時、再灌流時の代謝産物の放出、遅延相にのみ起こる酸化脂質の蓄積などから、新しい治療標的の同定に成功した(図4)。これらの成果を踏まえ、臨床現場で実現可能な治療となりうる薬物または医療機器の開発につなげる研究の加速が期待される。