Cross-talk of cardiomyocyte necroptosis and autophagy in heart failure

• Project/Area Number: 18K08079
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Tetsuji Miura 札幌医科大学, 医学部, 教授 (90199951)
• Co-Investigator(Kenkyū-buntansha): 三木 隆幸 札幌医科大学, 医学部, 准教授 (00336405) ; 丹野 雅也 札幌医科大学, 医学部, 准教授 (00398322) ; 矢野 俊之 札幌医科大学, 医学部, 講師 (40444913)
• 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 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 細胞死 / 細胞内情報伝達 / ネクロプトーシス / オートファジー / 心不全 / RIP1 / mTORC1 / TFEB / cell death / necroptosis / autophagy / heart failure / signal tranduction

Outline of Final Research Achievements

This study examined if necroptosis of cardiomyocytes contributes to progression of chronic heart failure and if dysregulation of lysosomes in autophagy is involved in necroptotic death of cardiomyocytes. Results of experiments using isolated cardiomyocytes indicated that inflammatory cytokines, but not other humoral factors, mainly trigger necroptotic signaling and that there are two mechanisms of necroptotic cell death downstream of the signaling, cell membrane damages and suppression of autophagy via inhibition of a master transcriptional factor of lysosomes, in cardiomyocytes. Involvement of necroptotic signaling in chronic heart failure was supported by results of immun-ohistochemical analysis of endomyocardial biopsies from patients.

Academic Significance and Societal Importance of the Research Achievements

慢性心不全における心筋細胞死は心不全を不可逆的に進行させる原因であり、心筋細胞死の抑制は重症心不全に対する新たな治療の開発に極めて重要である。本研究は、慢性心不全で増加する複数の生物活性物質のうち炎症性サイトカインが心筋細胞のネクロプトーシス（プログラム細胞死）を誘導するものとして重要であることと、ネクロプトーシスの機序としてこれまで知られていた細胞膜障害に加えリソソーム機能制御の障害が重要であることを示した。この成果は、心筋細胞ネクロプトーシス抑制のための治療標的分子に示唆を与えるとともに、細胞死を制御するオルガネラとしてのリソソームの新たな機能を明らかにした意義がある。

Research Products

• [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] Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload (2021)
  • Author(s): Igaki Yusuke、Tanno Masaya、Sato Tatsuya、Kouzu Hidemichi、Ogawa Toshifumi、Osanami Arata、Yano Toshiyuki、Kuno Atsushi、Miki Takayuki、Nakamura Takashi、Miura Tetsuji
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 154 Pages: 21-31
  • DOI: 10.1016/j.yjmcc.2021.01.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of the angiotensin II receptor promotes autophagy in renal proximal tubular cells and affords protection from ischemia/reperfusion injury (2021)
  • Author(s): Sugawara Hirohito、Moniwa Norihito、Kuno Atsushi、Ohwada Wataru、Osanami Arata、Shibata Satoru、Kimura Yukishige、Abe Koki、Gocho Yufu、Tanno Masaya、Miura Tetsuji
  • Journal Title: Journal of Pharmacological Sciences Volume: 145 Issue: 2 Pages: 187-197
  • DOI: 10.1016/j.jphs.2020.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-1 (2020)
  • Author(s): Ohwada W, Tanno M, Yano T, Ong SB, Abe K, Sato T, Kuno A, Miki T, Sugawara H, Igaki Y, Miura T.
  • Journal Title: Biochim Biophys Acta Mol Basis Dis Volume: 1866 Issue: 10 Pages: 165851-165851
  • DOI: 10.1016/j.bbadis.2020.165851
  • Peer Reviewed / Open Access
• [Journal Article] mTORC1 Inhibition Attenuates Necroptosis Through RIP1 Inhibition-Mediated TFEB Activation (2019)
  • Author(s): Abe K, Yano T, Tanno M, Miki T, Kuno A, Sato T, Kouzu H, Nakata K, Ohwada W, Kimura Y, Sugawara H, Shibata S, Igaki Y, Ino S, Miura T.
  • Journal Title: Biochim Biophys Acta Mol Basis Dis . Volume: 1865 Issue: 12 Pages: 165552-165552
  • DOI: 10.1016/j.bbadis.2019.165552
  • Peer Reviewed
• [Journal Article] Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts. (2018)
  • Author(s): Tatekoshi Y, Tanno M, Kouzu H, Abe K, Miki T, Kuno A, Yano T, Ishikawa S, Ohwada W, Sato T, Niinuma T, Suzuki H, Miura T.
  • Journal Title: J Mol Cell Cardiol Volume: 119 Pages: 138-146
  • DOI: 10.1016/j.yjmcc.2018.05.003
  • Peer Reviewed
• [Journal Article] Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. (2018)
  • Author(s): Mizuno M, Kuno A, Yano T, Miki T, Oshima H, Sato T, Nakata K, Kimura Y, Tanno M, Miura T
  • Journal Title: Physiological Reports Volume: 6 Issue: 12 Pages: e13741-e13741
  • DOI: 10.14814/phy2.13741
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Does p53 Inhibition Suppress Myocardial Ischemia-Reperfusion Injury? (2018)
  • Author(s): Yano T, Abe K, Tanno M, Miki T, Kuno A, Miura T, Steenbergen C
  • Journal Title: J Cardiovasc Pharmacol Ther Volume: 印刷中 Issue: 4 Pages: 350-357
  • DOI: 10.1177/1074248418763612
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Phosphorylated MLKL, an Executor of Necroptosis, Localized in the Nucleus and Intercalated Disc Plays Distinct Roles in Nonischemic Dilated Cardiomyopathy. (2020)
  • Author(s): Fujita Y, Yano T, Nagano N, Nishikawa R, Kamiyama N, Fujito T, Mochizuki A, Koyama M, Kouzu H, Muranaka A, Nagahara D, Tannno M, Miki T, Miura T.
  • Organizer: 第84回日本循環器学会年次学術集会
• [Presentation] Plasma valine-to-glycine ratio is a novel prognostic maker for adverse events in patients with heart failure (2020)
  • Author(s): Kouzu H, Katano S, Yano T, Ohori K, Honma S, Shimomura K, Inoue T, Takamura Y, Takahashi R, Nishikawa R, Nagano N, Koyama M, Fujito T, Hashimoto A, Miura T.
  • Organizer: 第84回日本循環器学会年次学術集会
• [Presentation] Alterations in Mitochondrial Function by SGLT2 Inhibitors (2020)
  • Author(s): Miura T
  • Organizer: American Society of Nephrology(ASN) Kidney Week 2020
  • Invited
• [Presentation] Inhibition of xanthine oxidase ameliorates functional and metabolic impairment in type 2 diabetic hearts under pressure overload. (2020)
  • Author(s): Igaki Y, Osanami A, Tanno M, Sato T, Ogawa T, Yano T, Kouzu H, Miura T
  • Organizer: European Society of Cardiology Congress 2020
• [Presentation] Novel regulation of cardiac branched-chain amino acid metabolism through AMP deaminase: A possible therapeutic target for diabetic cardiomyopathy. (2020)
  • Author(s): Ogawa T, Kouzu H, Tatekoshi Y, Osanami A, Oshima H, Mizuno M, Kuno A, Igaki Y, Sugawara H, Fujita Y, Sato T, Yano T, Tanno M, Miki T, Miura T.
  • Organizer: European Society of Cardiology Congress 2020
• [Presentation] Cardioprotection-Autophagy and Mitochondrial Signaling pathways in cardioprotection (2019)
  • Author(s): Tetsuji Miura
  • Organizer: 2019 XXIII ISHR World Congress,Beijing, China.
• [Presentation] Activation of necroptotic pasthway by downregulated caspase-8 expression is associated with progression of left ventricular remodeling in nonischemic dilated cardiomyopathy. (2019)
  • Author(s): Fujita Y, Yano T, Abe K, Nagano N, Kamiyama N, Fujito T, Mochizuki A, Koyama M, Kouzu H, Muranaka A, Nagahara D, Tanno M, Miki T, Miura T
  • Organizer: ESC congress 2019. Paris, France.
• [Presentation] mTORC1 inhibition suppresses necroptosis through restroration of autophagic flux by inhibitory phosphorylation of RIP1 in cardiomyocytes. (2018)
  • Author(s): Abe K, Yano T, Miki T, Tanno M, Kuno A, Sato T, Mizuno M, Miura T.
  • Organizer: European Society of Cardiology Congress
  • Int'l Joint Research
• [Presentation] Inhibition of mTORC1 supresses necroptosis of cardiomyocytes in a p70S6K-independent mechanism by suppression of p62-RIP1 interaction. (2018)
  • Author(s): Abe K, Yano T, Miki T, Tanno M, Kuno A, Sato T, Miura T.
  • Organizer: 日本循環器学会学術集会
• [Presentation] Crosstalk between Aberrant mTORC1 Activation and Necroptotic Pathway: a Novel Therapeutic Target in Ischemic Heart Disease (2018)
  • Author(s): Yano T, Abe K, Ogasawara M, Kuno A, Tanno M, Miki T, Miura T.
  • Organizer: 日本循環器学会学術集会
• [Presentation] mTORC1 suppresses cardiomyocyte necroptosis through autophagy and RIP1 inhibition (2018)
  • Author(s): Abe K, Yano T, Miki T, Tanno M, Kuno A, Sato T, Miura T.
  • Organizer: 日本循環器学会基礎医学フォーラム