The elucidation of the molecular mechanisms of heart failure after myocardial infarction and the proposal of novel therapeutic targets for heart failure

• Project/Area Number: 19K23800
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Osaka University
• Principal Investigator: Matsumoto Kotaro 大阪大学, 薬学研究科, 招へい研究員 (90849879)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心不全 / 心筋梗塞 / 炎症関連免疫細胞 / 炎症性免疫細胞 / ミエロイド細胞 / シングルセル解析 / 虚血性心疾患 / 炎症 / シングルセルRNA-seq解析

Outline of Research at the Start

本研究では、心筋梗塞発症時に心臓組織に浸潤する免疫細胞によって引き起こされる炎症・線維化反応の機序を明らかにすることを目的に以下の3点を行う。
① 梗塞心に浸潤するLRRC32+ or Thy1+ or FSCN1+ミエロイド細胞の性質の解明。
② 梗塞心におけるTGF-β3の機能解析。
③ LRRC32+ or Thy1+ or FSCN1+ミエロイド細胞欠損マウスの病態解析。

Outline of Final Research Achievements

Cardiac remodeling is positively and negatively regulated by inflammatory immune cells; however, the molecular mechanisms are not fully understood. In the present study, novel myeloid cells expressing TGF-β3 and Glycoprotein A Repetitions Predominant (GARP) were found by single cell RNA-sequencing. The expression of TGF-β3 and GARP was increased in murine hearts after myocardial infarction (MI). Moreover, anti-TGF-β3 antibody treatment suppressed cardiac dysfunction and adverse cardiac remodeling 14 days after MI. Therefore, the myeloid cells expressing TGF-β3 and GARP may play a crucial role in cardiac remodeling. Future studies will assess the role of TGF-β3 and GARP in myeloid cells in cardiac remodeling using cell specific knockout mice.

Academic Significance and Societal Importance of the Research Achievements

心疾患は我が国の死因別死亡率の第2位を占める。また、超高齢社会を迎えた我が国では、心不全パンデミックと称されるように、心不全患者が急増している。現在の治療を以てしても、心不全は予後不良の病態であるため、新たな心不全発症予防法の確立が重要である。本研究では、心筋梗塞後の心不全発症過程に、これまで知られていなかった炎症関連免疫細胞が関与する可能性を見出した。本研究成果は、新たな心不全治療標的の提唱に繋がると期待される。

Research Products

• [Presentation] Inhibition of transcription factor OASIS attenuated kidney fibrosis. (2020)
  • Author(s): Ayaha Yamamoto, Masanori Obana, Takafumi Nakae, Yoshiaki Miyake, Sayuri Mitsuoka, Makiko Maeda, Kazunori Imaizumi, Kotaro Matsumoto, Yasushi Fujio.
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Maresin 1, an anti-inflammatory lipid mediator, induces physiological hypertrophy in neonatal rat cardiomyocytes. (2020)
  • Author(s): Arisa Kobayashi, Wahyuni Tri, Ryuta Igarashi, Masashi Tomimatsu, Kotaro Matsumoto, Makiko Maeda, Masanori Obana, Yasushi Fujio.
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Development of a screening system for the compounds that induce the cell cycle activity in mammalian cardiomyocytes. (2020)
  • Author(s): Risa Matsui, Shoki Fukuyama, Yusuke Kametani, Yuriko Wada, Kotaro Matsumoto, Makiko Maeda, Masanori Obana, Yasushi Fujio.
  • Organizer: 第93回日本薬理学会年会
• [Presentation] β2-adrenergic stimulation induces Arid5a through cAMP/PKA/CREB axis to promote IL-6 upregulation. (2020)
  • Author(s): Shota Tanaka, Atsuki Imaeda, Kotaro Matsumoto, Makiko Maeda, Masanori Obana, Yasushi Fujio.
  • Organizer: 第93回日本薬理学会年会
• [Presentation] β2 adrenergic signaling of cardiac fibroblasts induces cardiac hypertrophy through paracrine system. (2020)
  • Author(s): Atsuki Imaeda, Shota Tanaka, Kotaro Matsumoto, Makiko Maeda, Masanori Obana, Yasushi Fujio.
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 炎症抑制脂質分子Maresin1は新生児ラット培養心筋細胞において生理的肥大を惹起する (2020)
  • Author(s): 小林亜里沙、トリワヒュニ、五十嵐竜太、冨松聖史、松本浩太朗、前田真貴子、尾花理徳、藤尾慈
  • Organizer: 第93回日本薬理学会年会