2019 Fiscal Year Final Research Report
Pathophysiological significance of mechanisms underlying metabolic remodeling of hypertrophied heart
| Project/Area Number |
17K09568
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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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| Research Field |
Cardiovascular medicine
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| Research Institution | Gunma University |
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Principal Investigator |
Iso Tatsuya 群馬大学, 大学院医学系研究科, 研究員 (10400756)
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| Co-Investigator(Kenkyū-buntansha) |
大日方 英 群馬大学, 大学院医学系研究科, 准教授 (50332557)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 心肥大 / 構造リモデリング / 代謝リモデリング / 脂肪酸代謝 / グルコース代謝 / 心不全 |
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| Outline of Final Research Achievements |
Under increased workload, the heart shows structural (cardiac hypertrophy
and fibrosis) and metabolic remodeling. However, little was unknown about a link between structural and metabolic remodeling. FABP4/5 double knockout and CD36 knockout mice exhibit reduced fatty acid (FA) use with a marked increase in glucose uptake in hearts. When hearts were pressure-overloaded, cardiac dysfunction was exacerbated in both mice. Metabolic analysis revealed that total energy supply was reduced despite a further increase in glucose uptake, leading to a reduction in ATP synthesis. In contrast, de novo synthesis of biomaterials for cardiac hypertrophy (i.e. amino acids and nucleic acids) was facilitated. Synthesis of glycerophospholipid, a component of membrane structure, was likely to depend on exogenous FA uptake. Thus, the heart favors anabolic reactions rather than ATP synthesis during the development of cardiac hypertrophy even under conditions where total energy supply is limited.
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| Free Research Field |
循環器内科学
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| Academic Significance and Societal Importance of the Research Achievements |
心臓のエネルギー代謝をATP産生経路と非ATP産生経路の両面から、全体像を俯瞰してin vivo実験を重ねることで、心肥大形成の際のアミノ酸・脂肪酸・核酸の生合成の問題点に到達した。心機能の維持にとって、心筋細胞の収縮連関に直接関与するATP産生以外にも、組織構築の維持や補強に必須の生体分子の生合成が重要な役割をはたすことを明らかにした意義は大きい。また、従来のランゲンドルフ還流心（ex vivo実験）では得られない実験結果を、in vivo実験で提示できた点は特筆に値する。In vivo心筋の代謝変化の全体像を理解することで、心不全治療開発戦略の包括的なアプローチを促進するものと考える。
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