2023 Fiscal Year Final Research Report
Elucidation of regulatory mechanisms of glutamine metabolism in heart failure and development of novel therapeutic strategies
| Project/Area Number |
21K08105
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
杜 隆嗣 神戸大学, 医学研究科, 特命准教授 (50379418)
長尾 学 神戸大学, 医学研究科, 特命助教 (70866029)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | グルタミノリシス / 心筋代謝 / 心不全 / グルタミナーゼ1 / グルタミン |
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| Outline of Final Research Achievements |
Glutamine-derived anaplerosis, also known as glutaminolysis, is strongly associated with the pathophysiology of various diseases represented by cancer. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was increased in angiotensin II (Ang II)-induced mouse hearts and cultured rat cardiac cells, and anaplerotic glutamine flux into the tricarboxylic acid (TCA) cycle was markedly enhanced in cardiomyocytes, suggesting that glutaminolysis is activated in failing hearts. GLS1 inhibition improved Ang II-induced cardiac hypertrophy and fibrosis in vitro and in vivo, possibly by reducing the production of glutamine-derived aspartate and citrate, which are used for the biosynthesis of nucleotides and lipids required for cellular growth and proliferation. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibiting this anaplerotic pathway could be a novel therapeutic approach for HF.
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| Free Research Field |
心筋代謝
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| Academic Significance and Societal Importance of the Research Achievements |
心不全は心血管疾患すべての終末像であり、心不全患者数は全世界的に増加の一途をたどっている。本邦においても2040年頃まで新規心不全患者の発症数は増加するとことが予測され、医療経済の観点でも大きな社会問題となっている。心不全治療薬の多くは、交感神経系や液性因子を標的としたもので、代謝経路を直接的な標的とした治療薬は存在しない。このような中、本研究ではグルタミン代謝経路に着目し、その阻害が心肥大や心臓線維化を抑制することを証明した。これは全く新しい知見であり、今後新たな心不全治療薬の創薬へと繋がる意義深い研究である。
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