Investigation for a molecular regulatory mechanism inducing endogenous myocardial inflammation

• Project/Area Number: 18H02807
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Osaka University
• Principal Investigator: OTSU Kinya 大阪大学, 医学系研究科, 招へい教授 (20294051)
• Co-Investigator(Kenkyū-buntansha): 種池 学 大阪大学, 医学系研究科, 助教 (30609756) ; 山口 修 大阪大学, 医学系研究科, 招へい教授 (90467580)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 心不全 / 炎症 / ミトコンドリア / 心筋炎症

Outline of Final Research Achievements

Inflammation plays an important role in the development and progression of heart failure. We investigated a molecular mechanism in the induction of sterile inflammation to find a novel therapeutic target for the treatment to heart failure. 1) We identified a microRNA that regulates the expression of DNase II, which degrades inflammatogenic mitochondrial DNA. In addition, we revealed that the microRNA is related to the pathogenesis of heart failure in a mouse heart failure model. 2) It was revealed that HMGB1 is related to the development of heart failure through the induction of inflammation. 3) We reported that an TLR9 inhibitor attenuates the development and progression of heart failure in mice, and that cytokine mRNA degradation in cardiomyocytes regulates inflammation in the heart.

Academic Significance and Societal Importance of the Research Achievements

これまで、炎症メカニズムの下流に位置するサイトカインに対する介入では心不全の予後改善効果を得られなかった。本研究では、当該microRNAとHMGB1のいずれもが心不全発症進展メカニズムの一つである無菌性炎症に関わっており、炎症メカニズムの上流に位置する分子経路への介入が心不全治療標的となり得る可能性について示した。これらの結果は、今後の新しい心不全治療戦略に繋がることが期待され、学術的にも社会的にも意義深い。

Research Products

• [Int'l Joint Research] King's College London(英国)
• [Int'l Joint Research] King's College London(英国)
• [Int'l Joint Research] King's College London(英国)
• [Journal Article] Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice (2021)
  • Author(s): Ito Jumpei、Omiya Shigemiki、Rusu Mara-Camelia、Ueda Hiromichi、Murakawa Tomokazu、Tanada Yohei、Abe Hajime、Nakahara Kazuki、Asahi Michio、Taneike Manabu、Nishida Kazuhiko、Shah Ajay M、Otsu Kinya
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.62174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1 (2021)
  • Author(s): Daniel J Klionsky、Shu Aizawa、Amal Kamal Abdel-Aziz、Sara Abdelfatah、Mahmoud Abdellatif、Asghar Abdoli、Steffen Abel、Hagai Abeliovich、Marie H Abildgaard、Yakubu Princely Abudu、Abraham Acevedo-Arozena、Iannis E Adamopoulos、Khosrow Adeli、Timon E Adolph、Annagrazia Adornetto、Elma Aflaki、Galila Agam et al.
  • Journal Title: Autophagy Volume: 17 Issue: 1 Pages: 1-382
  • DOI: 10.1080/15548627.2020.1797280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure-Overloaded Hearts (2020)
  • Author(s): Omiya Shigemiki、Omori Yosuke、Taneike Manabu、Murakawa Tomokazu、Ito Jumpei、Tanada Yohei、Nishida Kazuhiko、Yamaguchi Osamu、Satoh Takashi、Shah Ajay M.、Akira Shizuo、Otsu Kinya
  • Journal Title: Circulation Volume: 141 Issue: 8 Pages: 667-677
  • DOI: 10.1161/circulationaha.119.044582
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice (2019)
  • Author(s): Hiromichi Ueda, Osamu Yamaguchi, Manabu Taneike, Yasuhiro Akazawa, Haruko Wada-Kobayashi, Ryuta Sugihara, Hiroki Yorifuji, Hiroyuki Nakayama, Shigemiki Omiya, MD, Tomokazu Murakawa, Yasushi Sakata, Kinya Otsu
  • Journal Title: J Am Coll Cardiol Basic Trans Science Volume: 印刷中
  • Peer Reviewed / Open Access
• [Presentation] The role of autophagy in cardiac remodelling (2021)
  • Author(s): 大津欣也
  • Organizer: 第85回日本循環器学会学術集会
  • Invited
• [Presentation] Ferritin degradation mediated by autophagyleads to cardiomyocyte death and heart failure by inducing iron release in mouse pressure-overload hearts (2021)
  • Author(s): 種池学
  • Organizer: 第37回国際心臓研究学会日本部会