Developing therapeutic strategy targeting PDE1 against right heart failure

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17567
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyushu University
• Principal Investigator: Hashimoto Toru 九州大学, 大学病院, 助教 (00616617)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 右心不全 / PDE1 / 重症心不全 / PKA / PKG

Outline of Final Research Achievements

We established a mouse model of right ventricular failure (RVF) and demonstrated the critical roles of PDE1A, PDE1C, and PDE10A in the progression of RVF. We also demonstrated that the PDE1 was up-regulated in the myocardium of HFpEF mice, and that inhibition of PDE1 improved HFpEF phenotype. Activation of both cAMP-PKA and cGMP-PKG pathways was observed in PDE1-inhibited in animals. These findings will be a basis for the development of treatment for RVF and HFpEF, for which treatment have not been established. We initially assumed the involvement of endoplasmic reticulum stress response, but significant modification was not observed in PDE1-inhibited animals. We got preliminary data suggesting the PDE1 regulation of intracellular calcium dynamics and subsequent myocyte dysfunction. Further studies are planned to elucidate the precise intracellular mechanism of PDE1-mediated pathobiology of RVF and HFpEF.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

左心不全、特にHFrEFには予後改善効果が証明された薬物療法・非薬物療法が多数存在するが、右心不全に関しては生命予後改善を大規模臨床研究で証明できた治療法が存在しない。一方でHFrEFであってもHFpEFであっても、右心機能低下を合併していると予後が不良であることが多数の報告で示されている。さらに重症心不全では補助人工心臓植込術という強力な非薬物療法が存在するにも関わらず、術後の右心不全で心不全症状が遷延する症例も多数存在する。したがって右心不全の新規治療開発は喫緊の課題である。本研究において右心不全におけるPDE1の役割を示したことにより、今後の治療法開発の基盤となることが期待される。