A Transient Up-regulation of Retinoic Acid Signaling Induces Cell Cycle Arrest in Neonatal Mammalian Heart

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: Unno Kazumasa 名古屋大学, 医学系研究科, 招へい教員 (40709119)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 心筋細胞 / 細胞分裂 / 核内受容体 / レチノイン酸 / 低酸素誘導因子 / エピゲノム修飾

Outline of Final Research Achievements

Several lines of evidence suggest that mammalian cardiomyocytes lose their ability of cell division during neonatal period, however, the underling mechanism is remained yet to be elucidated. We hypothesized that nuclear receptors play a role in the process of cell cycle arrest in neonatal cardiomyocyte. We found that all trans retinoic acid, a ligand of retinoic acid (RA) receptors,inhibits the cell cycle of cardiomyocyte. Moreover, Aldh1a2, a rate limiting enzyme of RA biosynthesis, is transiently upregulated peaking at postnatal day 6 in mouse heart. We also found that the gene expression of Aldh1a2 is under control of oxygen concentration through Hif1a, hypoxia inducible factor 1a. Accordingly, we conclude that increased tissue oxygen concentration degrades Hif1a which is negatively regulating the gene expression of Aldh1a2. Stimulated RA receptors,modulate cell cycle related gene expressions including Cyclin B1 or Cyclin D1, thereby inhibit cell cycle progression.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

ヒトを含む哺乳類の心筋細胞は分裂能が無く、心筋梗塞などで一旦その数が減ると再生されないと考えられてきた。しかし、最近の報告によると哺乳類の心筋細胞もその数は限られているが分裂能を有していることが明らかになってきた。この心筋細胞の分裂効率を上昇させることができれば残存心筋から心機能を回復するだけの心筋細胞を再生させることができるかもしれない。
研究代表者らの今回の研究は、心筋細胞の分裂能喪失という新生児期に起こる現象のメカニズムを検討することで、将来的に残存心筋の分裂能を再開させ心筋再生を治療応用できるレベルまで高めることを実現する端緒となる基礎研究であると考えられる。