Developing therapeutic strategy targeting PDE1 against right heart failure
Project/Area Number |
19K17567
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 53020:Cardiology-related
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Research Institution | Kyushu University |
Principal Investigator |
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Project Period (FY) |
2019-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | 右心不全 / PDE1 / 重症心不全 / PKA / PKG / PDE10A / 肺動脈縮窄 / cGMP / cAMP / cyclic nucleotide |
Outline of Research at the Start |
右心不全の病態におけるPDE1の役割を解明し、PDE1標的治療が既存の治療より有効であることを証明する。右心不全動物モデル(肺動脈縮窄ラット)にPDE1阻害薬を投与(急性投与、慢性投与、予防投与)して、血行動態測定、分子生物学的解析、病理組織学的、細胞生理学的解析を網羅的に行う。本研究の成果はPDE1を標的とする右心不全の新規治療法の基盤となり、患者の予後改善に役立つ。
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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.
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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。
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Report
(5 results)
Research Products
(44 results)
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[Journal Article] Undiagnosed Cardiac Sarcoidosis Causing Refractory Heart Failure After Acute Myocardial Infarction due to Thromboembolism2021
Author(s)
Takashi Kai, Yoshiyasu Ono, Shouji Matsushima, Keisuke Shinohara, Ryosuke Nakashima, Takuro Kawahara, Masato Katsuki, Takeo Fujino, Toru Hashimoto, Taiki Higo, Hiroyuki Tsutsui.
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Journal Title
International Heart Journal
Volume: 62
Issue: 2
Pages: 437-440
DOI
NAID
ISSN
1349-2365, 1349-3299
Year and Date
2021-03-30
Related Report
Peer Reviewed
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[Journal Article] The outcome of patients with functional single ventricular heart after pacemaker implantation - what makes it poor and what can we do?2019
Author(s)
Yoshihiko Kodama, Ayako Kuraoka, Yuichi Ishikawa, Makoto Nakamura, Hiroya Ushinohama, Koichi Sagawa, Shintaro Umemoto, Toru Hashimoto, Ichiro Sakamoto, Kisho Ohtani, Tomomi Ide, Hiroyuki Tsutsui, Shiro Ishikawa.
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Journal Title
Heart Rhythm
Volume: 16
Issue: 12
Pages: 1870-1874
DOI
Related Report
Peer Reviewed
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[Presentation] Long-term Outcomes of Heart Failure Patients with Preserved, Mildly Reduced, and Reduced Ejection Fraction: JROADHF2023
Author(s)
Takuya Nagata, Tomomi Ide, Takeshi Tohyama, Hidetaka Kaku, Nobuyuki Enzan, Shoji Matsushima, Masataka Ikeda, Shunsuke Katsuki, Yasuhiro Nakano, Toru Hashimoto, Tetsuya Matoba, Koji Todaka, Hiroyuki Tsutsui
Organizer
The 87th annual scientific meeting of the Japanese Circulation Society
Related Report
Int'l Joint Research
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[Presentation] Severity of vWF degradation depends on LVAD types; preliminary results from a multi-center prospective study2020
Author(s)
Zuo Y, Sakatsume K, Sasaki K, Nakajima S, Fukushima , Fujino T, Hashimoto T, Shiose A, Ooka T, Matsui Y, Watanabe M, Matsumiya G, Mutsuga M, Usui A, Fujiwara T, Arai H, Niinami N, Ono M, Sawa Y, Akiyama M, Horiuchi H, Saiki Y
Organizer
he 49th Annual Meeting of the German Society for Thoracic and Cardiovascular Surgery
Related Report
Int'l Joint Research
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