Elucidation of novel molecular mechanisms of the treatment strategy for heart failure by inactivating the DNA damage response

• Project/Area Number: 19K08560
• 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: Kumamoto University
• Principal Investigator: Miyata Keishi 熊本大学, 大学院生命科学研究部(医), 客員教授 (50398228)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 心不全 / DNA損傷応答

Outline of Research at the Start

近年心不全を発症した心筋細胞では断片化DNAの蓄積だけでなくDNA 損傷応答（DDR）活性化を認めており、DDR に誘導される炎症性サイトカイン活性が心不全悪化を促進しており、心不全病態形成においてDDR 活性化が重要な役割を果たしていることが明らかとなっている。しかし心不全病態形成においてDDR 活性化を制御する詳細な分子機構は十分に解明されていない。本研究ではDDR 制御関連遺伝子改変マウスを用いてモデルマウス作製し心不全病態形成におけるDDR 活性制御の詳細な分子機構の解明を行い、DDR 不活性化による心不全病態の進展を遅延あるいは阻止する新たな治療戦略の開発に繋がる研究基盤を確立する。

Outline of Final Research Achievements

Recently, cardiomyocytes that have developed heart failure show not only accumulation of fragmented DNA but also DNA damage response (DDR) activation is observed, and inflammatory cytokines induced by DDR exacerbate the development of heart failure. Although it has been clarified that DDR activation of cardiomyocytes plays an important role in the development of heart failure pathology, the detailed molecular mechanism that regulates DDR activation in cardiomyocytes is not fully elucidated. In this study, the analysis of heart failure model mice using DDR-related gene-modified mice revealed that reducing the expression of Hint1 in cardiomyocytes suppresses DDR activation in the development of heart failure and has a cardioprotective effect. Furthermore, reducing Hint1 expression was found to suppress the cardiotoxicity of adriamycin caused by DDR.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、依然として予後不良の疾患である心不全に対してDDR活性化抑制という新たな観点からの予防や新規治療法開発に繋がる可能性が期待される。さらに、近年、高齢化によって循環器疾患とがんを合併する患者が多く認められ、化学療法の進歩によりがんの治療率は格段に向上しているが、それに伴って薬剤による心毒性という副作用が問題となっている。本研究の成果はDDR活性化が原因とされるアドリアマイシンの心毒性の軽減にも繋がる可能性がある。

Research Products

• [Int'l Joint Research] University of Utah(米国)
• [Int'l Joint Research] ユタ大学(米国)
• [Int'l Joint Research] ユタ大学(米国)
• [Journal Article] Hyperglycemia and Thrombocytopenia ― Combinatorially Increase the Risk of Mortality in Patients With Acute Myocardial Infarction Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation ― (2021)
  • Author(s): Okadome Yusuke、Morinaga Jun、Fukami Hirotaka、Hori Kota、Ito Teruhiko、Sato Michio、Miyata Keishi、Kuwabara Takashige、Mukoyama Masashi、Suzuki Ryusuke、Tsunoda Ryusuke、Oike Yuichi
  • Journal Title: Circulation Reports Volume: 3 Issue: 12 Pages: 707-715
  • DOI: 10.1253/circrep.CR-21-0043
  • NAID: 130008128243
  • ISSN: 2434-0790
  • Year and Date: 2021-12-10
  • Peer Reviewed / Open Access
• [Journal Article] The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis (2021)
  • Author(s): Sato Michio, Kadomatsu Tsuyoshi, Miyata Keishi, Warren Junco S., Tian Zhe、Node Koichi、Araki Kimi、 Oike Yuichi et al
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2529-2529
  • DOI: 10.1038/s41467-021-22735-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia (2021)
  • Author(s): Fukami Hirotaka、Morinaga Jun、Nakagami Hironori、Hayashi Hiroki、Okadome Yusuke、Matsunaga Eiji、Kadomatsu Tsuyoshi、Horiguchi Haruki、Sato Michio、Sugizaki Taichi、Kuwabara Takashige、Miyata Keishi、Mukoyama Masashi、Morishita Ryuichi、Oike Yuichi
  • Journal Title: Cell Reports Medicine Volume: 2 Issue: 11 Pages: 100446-100446
  • DOI: 10.1016/j.xcrm.2021.100446
  • Peer Reviewed / Open Access
• [Journal Article] Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study. (2020)
  • Author(s): Fukami H, Morinaga J, Okadome Y, Nishiguchi Y, Iwata Y, Kanki T, Nakagawa T, Izumi Y, Kakizoe Y, Kuwabara T, Horiguchi H, Sato M, Kadomatsu T, Miyata K, Tajiri T, Oike Y, Mukoyama M.
  • Journal Title: Atherosclerosis. Volume: 315 Pages: 18-23
  • DOI: 10.1016/j.atherosclerosis.2020.10.890
  • Peer Reviewed / Open Access
• [Journal Article] Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia. (2020)
  • Author(s): Wei S, Isagawa T, Eguchi M, Sato D, Tsukano H, Miyata K, Oike Y, Takeda N, Ikeda S, Kawano H, Maemura K.
  • Journal Title: Biomedicines. Volume: 8(11) Issue: 11 Pages: 470-470
  • DOI: 10.3390/biomedicines8110470
  • Peer Reviewed / Open Access
• [Journal Article] Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis (2020)
  • Author(s): Horiguchi Haruki、Kadomatsu Tsuyoshi、Miyata Keishi、Terada Kazutoyo、Sato Michio、Torigoe Daisuke、Morinaga Jun、Moroishi Toshiro、Oike Yuichi
  • Journal Title: Oncogene Volume: 40 Issue: 1 Pages: 55-67
  • DOI: 10.1038/s41388-020-01505-7
  • Peer Reviewed
• [Journal Article] Melinjo seed extract increases adiponectin multimerization in physiological and pathological conditions. (2020)
  • Author(s): K. Oniki, T. Kawakami, A. Nakashima, K. Miyata, T. Watanabe, H. Fujikawa, R. Nakashima, A. Nasu, Y. Eto, N. Takahashi, H. Nohara, M. Ann Suico, S. Kotani, Y. Obata, Y. Sakamoto, Y. Seguchi, J. Saruwatari, T. Imafuku, H. Watanabe, T. Maruyama, H. Kai, T. Shuto
  • Journal Title: Scientific reports Volume: 10 Issue: 1 Pages: 4313-4313
  • DOI: 10.1038/s41598-020-61148-2
  • Peer Reviewed / Open Access
• [Journal Article] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study (2019)
  • Author(s): Morinaga J, Kakuma T, Fukami H, Hayata M, Uchimura K, Mizumoto T, Kakizoe Y, Miyoshi T, Shiraishi N, Adachi M, Izumi Y, Kuwabara T, Okadome Y, Sato M, Horiguchi H, Sugizaki T, Kadomatsu T, Miyata K, Tajiri S, Tajiri T, Tomita K, Kitamura K, Oike Y, Mukoyama M.
  • Journal Title: Nephrology Dialysis Transplantation Volume: 印刷中 Issue: 5 Pages: 854-860
  • DOI: 10.1093/ndt/gfz236
  • Peer Reviewed / Open Access
• [Journal Article] Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy (2019)
  • Author(s): Zhu Shunshun、Tian Zhe、Torigoe Daisuke、Zhao Jiabin、Xie Peiyu、Sugizaki Taichi、Sato Michio、Horiguchi Haruki、Terada Kazutoyo、Kadomatsu Tsuyoshi、Miyata Keishi、Oike Yuichi
  • Journal Title: PLOS ONE Volume: 14 Issue: 8 Pages: e0221366-e0221366
  • DOI: 10.1371/journal.pone.0221366
  • Peer Reviewed / Open Access
• [Journal Article] Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity. (2019)
  • Author(s): Horiguchi H, Kadomatsu T, Kurahashi R, Hara C, Miyata K, Baba M, Osumi H, Terada K, Araki K, Takai T, Kamba T, Linehan WM, Moroishi T, Oike Y.
  • Journal Title: Genes Dev Volume: 33 Issue: 23-24 Pages: 1641-1656
  • DOI: 10.1101/gad.329417.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MiR-204-5p: a novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma. (2019)
  • Author(s): Kurahashi R, Kadomatsu T, Baba M, Hara C, Itoh H, Miyata K, Endo M, Morinaga J, Terada K, Araki K, Eto M, Schmidt LS, Kamba T, Linehan WM, Oike Y.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 6 Pages: 1897-1908
  • DOI: 10.1111/cas.14026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The IncRNA Caren Protects Against Heart Failure by Inactivating the ATM-DNA Damage Response Pathway and Activating Mitochondrial Biogenesis (2021)
  • Author(s): Sato Michio, Keishi Miyata, Yuichi Oike
  • Organizer: 第85回日本循環器学会学術集会