Development of a new heart failure drug targeting ATP

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16071
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyoto University
• Principal Investigator: Tsuji Shuhei 京都大学, 医学研究科, 客員研究員 (70911915)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 心不全 / ATP / 強心作用 / 心保護作用

Outline of Final Research Achievements

Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a TAC-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

心不全は進行することで心筋細胞のATPレベルが低下し、心収縮力が低下する。心収縮力を急性期に改善させる薬剤としては強心薬があるが、強心薬はATP消費量を増加させることで最終的にATPレベルがさらに低下すること、また使用した患者では予後が悪化するなどの問題点が多い。一方で心不全の予後改善薬として使用されているβ遮断薬は心筋細胞のATP消費量を減らす作用があることが知られているが、陰性変力作用により初期には心収縮力を低下させ急性期の心不全治療には適していない。一方で心筋細胞のATPレベルを上昇させる薬剤は現在存在していない。ATPを上昇させる薬剤の効果を明らかにしたことで新規治療薬の可能性がある。