Studies on the roles of HSP90AA1 in failing heart

• Project/Area Number: 19K16379
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Marunouchi Tetsuro 東京薬科大学, 薬学部, 講師 (50548500)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: HSP90AA1 / 慢性心不全 / 心リモデリング / タンパク質間相互作用 / Hsp90 / 心不全 / ネクロトーシス / HSP90 / 心線維化 / 心筋リモデリング / 心筋細胞死 / 心筋幹・前駆細胞

Outline of Research at the Start

心不全は，様々な循環器疾患の進行に伴い，心臓の肥大化や線維化，心筋の細胞死などの有害な事象を引き起こし，心臓が正常に働けなくなった状態と定義される．私は，これらの事象の進展に，心臓の細胞内で様々なタンパク質の機能を制御する分子シャペロンタンパク質の HSP90AA1 が関与しているのではないかと仮説をたて，心不全モデル動物及び培養心筋細胞を用いて，心不全進展過程での HSP90AA1 の役割を解明するとともに，新たな心不全治療法の開発を目指した研究を計画している．

Outline of Final Research Achievements

Chronic heart failure is the final manifestation of various cardiovascular diseases, and novel therapies are needed due to its poor prognosis. HSP90AA1 is a molecular chaperone protein that regulates the activity of various intracellular signaling proteins. The expression of HSP90AA1 is markedly increased in the failing heart, suggesting that HSP90AA1 is involved in the development of heart failure. Therefore, we investigated the role of HSP90AA1 in the development of heart failure. In animal models of heart failure, we found that Hsp90 contributes to the activation of the MAP kinase and calcineurin/NFAT pathways involved in cardiac remodeling and the RIP/MLKL pathway involved in cell death. Furthermore, HSP90AA1 inhibitor treatment attenuates the activation of these pathways.
These results suggest that HSP90AA1 inhibition is a promising new treatment for heart failure.

Academic Significance and Societal Importance of the Research Achievements

HSP90AA1を治療標的とした心不全治療に関する新たな知見を示し，慢性心不全の治療法として“HSP90AA1阻害による細胞内情報伝達経路の制御”という新たな可能性を提示することができた．本研究で得られた知見を基礎として今後さらに発展させることで，細胞内情報伝達経路の制御を介した新規慢性心不全治療薬の開発研究が更に進展するものと期待される．

Research Products

• [Journal Article] Hsp90 Inhibitor Attenuates the Development of Pathophysiological Cardiac Fibrosis in Mouse Hypertrophy via Suppression of the Calcineurin-NFAT and c-Raf-Erk Pathways (2021)
  • Author(s): Marunouchi Tetsuro、Nakashima Miyuki、Ebitani Saika、Umezu Sakiko、Karasawa Kasane、Yano Emi、Tanonaka Kouichi
  • Journal Title: Journal of Cardiovascular Pharmacology Volume: 77 Issue: 6 Pages: 822-829
  • DOI: 10.1097/fjc.0000000000001017
  • Peer Reviewed
• [Journal Article] Effects of 17-AAG on the RIP1/RIP3/MLKL pathway during the development of heart failure following myocardial infarction in rats (2021)
  • Author(s): Marunouchi Tetsuro、Ito Takumi、Onda Sumika、Kyo Lina、Takahashi Kirara、Uchida Manami、Yano Emi、Tanonaka Kouichi
  • Journal Title: Journal of Pharmacological Sciences Volume: 147 Issue: 2 Pages: 192-199
  • DOI: 10.1016/j.jphs.2021.06.009
  • Peer Reviewed
• [Journal Article] Effects of Hsp90 inhibitor on the RIP1-RIP3-MLKL pathway during the development of heart failure in mice (2021)
  • Author(s): Marunouchi Tetsuro、Nishiumi Chiharu、Iinuma Saki、Yano Emi、Tanonaka Kouichi
  • Journal Title: European Journal of Pharmacology Volume: 898 Pages: 173987-173987
  • DOI: 10.1016/j.ejphar.2021.173987
  • Peer Reviewed
• [Journal Article] Transplantation of cardiac Sca-1-positive cells rather than c-Kit-positive cells preserves mitochondrial oxygen consumption of the viable myocardium following myocardial infarction in rats (2019)
  • Author(s): Marunouchi Tetsuro、Sasaki Kyohei、Yano Emi、Tanonaka Kouichi
  • Journal Title: Journal of Pharmacological Sciences Volume: 140 Issue: 3 Pages: 236-241
  • DOI: 10.1016/j.jphs.2019.07.005
  • Peer Reviewed / Open Access
• [Presentation] 心筋リモデリングでのHsp90の役割の解明と新規治療法への応用 (2021)
  • Author(s): 丸ノ内 徹郎
  • Organizer: 日本薬学会薬理系薬学部会 生体機能と創薬シンポジウム 2021
• [Presentation] Simvastatin attenuates cardiac remodeling via Hsp90 inhibition. (2021)
  • Author(s): 内田 愛美、丸ノ内 徹郎、藤田 喬、矢野 絵美、田野中 浩一
  • Organizer: 第95回 日本薬理学会年会
• [Presentation] シンバスタチンは，Hsp90の阻害を介して心線維化を抑制する (2021)
  • Author(s): 小野 亜弓、藤田 喬、丸ノ内 徹郎、田野中 浩一
  • Organizer: 日本薬学会 第142年会
• [Presentation] Hsp90 contributes to cardiac hypertrophy in the development of heart failure via regulating c-Raf. (2020)
  • Author(s): Takumi Itoh, Tetsuro Marunouchi, Emi Yano and Kouichi Tanonaka
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Tanshinone VI promotes the differentiation of cardiosphere-derived cells into cardiomyocytes. (2020)
  • Author(s): Tetsuro Marunouchi, Minami Ikoshi, Emi Yano and Kouichi Tanonaka
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Roles of Hsp90 on cardiac remodeling in the development of chronic heart failure. (2019)
  • Author(s): Yumi Abe, Tetsuro Marunouchi, Emi Yano and Kouichi Tanonaka
  • Organizer: 第93回日本薬理学会年会
• [Presentation] マウス圧負荷誘発心不全へのネクロプトーシスの関与 (2019)
  • Author(s): 丸ノ内 徹郎，矢野 絵美，田野中 浩一
  • Organizer: 日本薬学会第140年会