Relationship between deacetylation of nuclear High-Mobility Group Box 1 and Sirt7 activation in failing heart

• Project/Area Number: 18K08059
• 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: Yamagata University
• Principal Investigator: Kubota Isao 山形大学, 学内共同利用施設等, 理事 (30161673)
• Co-Investigator(Kenkyū-buntansha): 宍戸 哲郎 山形大学, 医学部, 客員研究員 (60400545)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 核内 HMGB1 / 心不全 / Sirt7 / 脱アセチル化 / アセチル化 / 翻訳後修飾

Outline of Final Research Achievements

HMGB1 is a DNA-binding protein associated with nuclear homeostasis and DNA repair. Decreased nuclear HMGB1 and Sirt7 expression were observed in the pressure-overload heart failure mouse model. Decreased nuclear HMBG1 and Sirt7 expression were also confirmed in patients with heart failure. Nuclear HMGB1 was acetylated and translocated to extracellular from intracellular as heart failure progresses, which attenuated the protective effect of nuclear HMGB1. We investigated the role of Sirt7 in deacetylation of HMGB1 and cardiac function in the heart failure model.

Academic Significance and Societal Importance of the Research Achievements

核内 HMGB1は心筋細胞の恒常性制御機構に重要な役割を果たす。我々は核内 HMGB1のアセチル化が心筋細胞に与える効果を検討し、心不全進展機構の解明を行ってきた。感染、糖尿病、虚血、圧負荷、加齢などのストレスによって、持続的にHMGB1 のアセチル化が生じている。HMGB1 の脱アセチル化機構の解明により、治療抵抗性の心不全やリバースリモデリングを得るための治療法の開発に繋がる可能性がある。

Research Products

• [Journal Article] Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response (2019)
  • Author(s): Tetsuya Takahashi, Tetsuro Shishido, Daisuke Kinoshita, Ken Watanabe, Taku Toshima, Takayuki Sugai, Taro Narumi, Yoichiro Otaki, Harutoshi Tamura, Satoshi Nishiyama, Takanori Arimoto, Hiroki Takahashi, Takuya Miyamoto, Tetsu Watanabe, Chang-Hoon Woo, Jun-ichi Abe, Yasuchika Takeishi, Isao Kubota and Masafumi Watanabe
  • Journal Title: JACC: Basic to Translational Science Volume: 4 Issue: 2 Pages: 234-234
  • DOI: 10.1016/j.jacbts.2018.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ventricular wall stress and silent myocardial damage are associated with pulse pressure in the general population. (2018)
  • Author(s): Takahashi T, Shishido T, Watanabe K, Sugai T, Toshima T, Kinoshita D, Yokoyama M, Tamura H, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Watanabe T, Shibata Y, Konta T, Ueno Y, Kato T, Kayama T, Kubota I, Watanabe M.
  • Journal Title: J Clin Hypertens (Greenwich). Volume: 33 Issue: 9 Pages: 1319-1326
  • DOI: 10.1111/jch.13349
  • Peer Reviewed / Open Access
• [Presentation] Cardiac nuclear higt-mobility grop box 1 attenuates angiotesin Ⅱinduced pathological cardiac hypertrophy by inhibitting DAN damage response pathway. (2018)
  • Author(s): T.Takahashi
  • Organizer: ESC, Munich；2018.8
  • Int'l Joint Research