Elucidation of a novel pathogenic mechanism of heart failure progression mediated by trimeric G protein

• Project/Area Number: 20K17077
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyoto University
• Principal Investigator: Inazumi Hideaki 京都大学, 医学研究科, 医員 (10844037)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心不全 / Gタンパク / 循環器

Outline of Research at the Start

本申請研究は、これまで心血管病において注目されていなかった抑制性 G タンパク Gαo が不全心筋において共役しているGタンパク質共役型受容体(GPCR)を同定すること。
またその薬理的阻害や遺伝的抑制が、種々の心不全モデルマウスの表現型に及ぼす影響を評価することにより、心不全の発症・進展における三量体Gタンパク質シグナリングの未知の分子機序を明らかにし新規心不全治療・予防法の開発を目指すものである。

Outline of Final Research Achievements

By analyzing a proprietary mouse model of heart failure, we have discovered that Gαo, a subtype of the inhibitory G protein α subunit (Gαi/o) family, whose role in cardiovascular disease has not been clarified, is upregulated in failing ventricular muscle and contributes to the onset and progression of heart failure. In this study, we found that Gαo up-regulation alters the localization of L-type Ca channel currents in mouse ventricular myocytes (L-type Ca channel currents through the cell surface membrane, not T-tube, are increased) as a molecular mechanism. We also found that this was not due to the subcellular localization of L-type Ca channels but to changes in their activity.

Academic Significance and Societal Importance of the Research Achievements

私達はこれまで心血管病における役割が明らかでなかった抑制性Gタンパクサブユニット(Gαi/o)ファミリーのサブタイプの一つであるGαoが心筋細胞内のL型Caチャネルの局所活性を変化させることで心不全の発症・進展に寄与するという新知見を見出すことができました。本研究成果は高齢化により今後ますます増加が見込まれる心不全患者さんに対する新たな治療法の開発に繋がる可能性があると考えられます。

Research Products

• [Journal Article] NRSF/REST-Mediated Epigenomic Regulation in the Heart: Transcriptional Control of Natriuretic Peptides and Beyond. (2022)
  • Author(s): Inazumi H, Kuwahara K.
  • Journal Title: Biology (Basel). Volume: 11 Issue: 8 Pages: 1197-1197
  • DOI: 10.3390/biology11081197
  • Peer Reviewed / Open Access
• [Journal Article] NRSF- GNAO1 Pathway Contributes to the Regulation of Cardiac Ca 2+ Homeostasis (2022)
  • Author(s): Inazumi Hideaki、Kuwahara Koichiro、Nakagawa Yasuaki、et al.
  • Journal Title: Circulation Research Volume: 130 Issue: 2 Pages: 234-248
  • DOI: 10.1161/circresaha.121.318898
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] NRSF-GNAO1 Transcriptional Pathway Plays a Pivotal Role in the Regulation of Cardiac Ca2+ Homeostasis (2022)
  • Author(s): Hideaki Inazumi
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] 転写調節因子・エピゲノム制御因子に着目した心不全の病態解明 (2022)
  • Author(s): 稲住英明
  • Organizer: 第70回日本心臓病学会学術集会
  • Invited
• [Presentation] 転写調節因子NRSFを介した心不全進展の分子メカニズム (2022)
  • Author(s): 稲住英明, 桑原宏一郎, 中川靖章, 大矢未来, 木下秀之, 森内健司, 柳澤洋, 金森敬彦, 錦見俊雄, 中尾一和
  • Organizer: 第26回日本心血管内分泌代謝学会学術集会
• [Presentation] NRSF-GNAO1-CaMKII 転写制御回路の心筋リモデリング、Ca2+恒常性における意義 (2021)
  • Author(s): 稲住 英明
  • Organizer: 第31回日本循環薬理学会
• [Presentation] The significance of NRSF-GNAO1-CaMKII transcriptional circuit in myocardial remodeling (2021)
  • Author(s): Hideaki Inazumi
  • Organizer: 第38回国際心臓研究学会日本部会
  • Invited
• [Presentation] CaMK-NRSF-GNAO1 transcriptional circuits participates in the pathological cardiac remodeling (2020)
  • Author(s): Hideaki Inazumi
  • Organizer: Basic Cardiovascular Science (BCVS) 2020
  • Int'l Joint Research / Invited
• [Presentation] Increased Gαo Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca2+ Homeostasis (2020)
  • Author(s): Hideaki Inazumi, Yasuaki Nakagawa, Kenji Moriuchi, Koichiro Kuwahara
  • Organizer: Basic Cardiovascular Science (BCVS) 2020
  • Int'l Joint Research
• [Presentation] NRSF-GNAO1-CaMK2 axis exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis (2020)
  • Author(s): Hideaki Inazumi, Yoshihiro Kuwabara, Koichiro Kuwahara, Yasuaki Nakagawa, Hideyuki Kinoshita, Kenji Moriuchi, Hiromu Yanagisawa, Toshio Nishikimi, Miku Oya, Mitsuhiko Yamada, Toshihide Kashihara, Nagomi Kurebayashi, Masami Sugihara, Kazuwa Nakao , Takeshi Kimura
  • Organizer: European Society of Cardiology (ESC) 2020
  • Int'l Joint Research