Role of a functional SNP of the gene coding brain serotonin synthesis rate-limiting enzyme Tph2 in dilated cardiomyopathy

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08540
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: International University of Health and Welfare
• Principal Investigator: Morimoto Sachio 国際医療福祉大学, 福岡保健医療学部, 教授 (50202362)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 遺伝性拡張型心筋症 / ノックインマウス / 脳セロトニン機能 / 心臓突然死 / 心不全死

Outline of Final Research Achievements

Tryptophan hydroxylase 2 (TPH2) expressed specifically in the central nervous system is involved in serotonin synthesis in the brain as a rate-limiting enzyme. Inbred mice have a functional SNP C1473G in Tph2, with the activity being lower in BALB/c with G/G allele than in C57BL/6 with C/C allele. In this study, we examined the role of this SNP in the disease phenotype of knock-in mice with a dilated cardiomyopathy (DCM)-causing mutation deltaK210 in cTnT by creating single-gene congenic strain with Tph2 1473C/C or G/G allele. C57BL/6 DCM mice frequently suffered from sudden cardiac death (SCD) with no heart failure symptoms, whereas BALB/c DCM mice mostly died of congestive HF. Introduction of G/G allele into C57BL/6 DCM mice caused congestive HF death and extended the life expectancy. On the other hand, introduction of C/C allele into BALB/c DCM mice caused SCD. Present results suggest that brain serotonin function plays an important role in the disease phenotype of DCM.

Free Research Field

心臓生理学

Academic Significance and Societal Importance of the Research Achievements

「脳セロトニン機能がDCM疾患表現型に影響する可能性がある」というのは以前の薬理学的研究（Li et al. J Mol Cell Cardiol, 2012）から導いた我々独自の仮説である。本研究は、近交系マウスに存在する活性の異なるセロトニン合成律速酵素Tph2の遺伝子多型を利用してこの仮説をさらに支持する新たな科学的証拠を提供するものである。本研究の成果は心不全および心臓突然死の精神的な面からの予防法開発や心理的ストレスが心疾患を誘発するメカニズムの解明などに役立つものであると期待される。