Elucidation of the role of dopamine receptor D1 in the pathophysiology of heart failure

• Project/Area Number: 18K15881
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yamaguchi Toshihiro 東京大学, 医学部附属病院, 届出研究員 (50802394)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 心不全 / 不整脈 / ドパミン受容体

Outline of Final Research Achievements

The researchers identified the dopamine receptor D1 as a gene whose expression is markedly increased in both pressure-overload mouse models and heart failure patients through complex and comprehensive analysis of gene expression in cardiac tissue. We also performed functional analysis of mice lacking and forcibly expressing cardiac-specific dopamine receptors, and found that these receptors in the heart contribute to the development of fatal arrhythmias. In addition, phosphorylation of ryanodine receptors in cardiomyocytes was suggested to be involved in the mechanism of action. Furthermore, the expression of D1 receptors were increased in the patients with severe heart failure especially in those with a history of fatal arrhythmias, suggesting that D1 receptors are involved in the development of fatal arrhythmias during heart failure in humans.

Academic Significance and Societal Importance of the Research Achievements

心不全の基礎研究領域ではこれまでモデル動物を用いた研究が積み重ねられてきたが、従来の研究ではモデル動物とヒトの種差及び心不全の病態の差異が臨床応用における課題となってきた。研究者はこの課題を乗り越えるため、心不全モデル動物及びヒト心不全の両者において発現が著増する心臓ドパミン受容体に着目し、心筋細胞特異的遺伝子改変マウスの解析により同受容体が心不全時の致死的不整脈の発症に寄与していることを明らかとした。また、心不全患者のサンプル及び病歴の解析により、同受容体はヒトにおいても致死的不整脈の発症に寄与していることが示唆された。本研究は心不全患者の突然死を抑制する新規治療法の開発に繋がると考える。

Research Products

• [Journal Article] Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure (2020)
  • Author(s): Yamaguchi Toshihiro、Sumida Tomokazu S.、Nomura Seitaro、Satoh Masahiro、Higo Tomoaki、Ito Masamichi、Ko Toshiyuki、Fujita Kanna、Sweet Mary E.、Sanbe Atsushi、Yoshimi Kenji、Manabe Ichiro、Sasaoka Toshikuni、Taylor Matthew R. G.、Toko Haruhiro、Takimoto Eiki、Naito Atsuhiko T.、Komuro Issei
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4364-4364
  • DOI: 10.1038/s41467-020-18128-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] 慢性心不全患者で認められる突然死の原因を解明
  • URL: https://www.h.u-tokyo.ac.jp/press/__icsFiles/afieldfile/2020/09/01/20200901_release.pdf