The HECT-Type Ubiquitin E3 Ligase ITCH Interacts with Thioredoxin-Interacting Protein and Ameliorates Reactive Oxygen Species-Induced Cardiotoxicity

• Project/Area Number: 26893025
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Cardiovascular medicine
• Research Institution: Yamagata University
• Principal Investigator: Otaki Yoichiro 山形大学, 医学部, 医員 (80732693)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 酸化ストレス / ユビキチン / ITCH / 翻訳後修飾 / ユビキチン転移酵素 / 心筋梗塞 / ROS / Apoptosis / Myocardial infarction

Outline of Final Research Achievements

The HECT-Type ubiquitin E3 ligase ITCH is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin-interacting protein (TXNIP) is a negative regulator of thioredoxin system. We focused on the functional role of ubiquitin E3 ligase ITCH and its interaction with TXNIP to elucidate the mechanism of cardiotoxicity induced by ROS. Protein interaction between TXNIP and ITCH was confirmed by immunoprecipitation assays. Overexpression of ITCH increased proteasomal TXNIP degradation and inhibited ROS generation, p38 MAPK, p53, and subsequent intrinsic pathway apoptosis in ROS-induced cardiotoxicity. We generated ITCH transgenic mouse. In ITCH-Tg mice, cardiac dysfunction and remodeling were restored compared with wild-type littermates after Dox injection and myocardial infarction surgery. ITCH targets TXNIP for ubiquitin-proteasome degradation and ameliorates ROS-induced cardiotoxicity through the thioredoxin system.

Research Products

• [Journal Article] HECT‐Type Ubiquitin E3 Ligase ITCH Interacts With Thioredoxin‐Interacting Protein and Ameliorates Reactive Oxygen Species Induced Cardiotoxicity (2016)
  • Author(s): Yoichiro Otaki, Hiroki Takahashi, Tetsu Watanabe, Akira Funayama, Shunsuke Netsu, Yuki Honda, Taro Narumi, Shinpei Kadowaki, Hiromasa Hasegawa, Shintaro Honda, Takanori Arimoto, Tetsuro Shishido, Takuya Miyamoto, Hideaki Kamata, Osamu Nakajima, Isao Kubota
  • Journal Title: Am Heart Assoc. Volume: 5 Issue: 1
  • DOI: 10.1161/jaha.115.002485
  • Peer Reviewed / Open Access
• [Journal Article] Comorbid renal tubular damage and hypoalbuminemia exacerbate cardiac prognosis in patients with chronic heart failure (2016)
  • Author(s): Yoichiro Otaki, Tetsu Watanabe, Hiroki Takahashi, Akira Funayama, Daisuke Kinoshita, Miyuki Yokoyama, Tetsuya Takahashi, Satoshi Nishiyama, Takanori Arimoto, Tetsuro Shishido, Takuya Miyamoto, Tsuneo Konta, Isao Kubota.
  • Journal Title: Clinical reseaarch of Cardioogy Volume: 105 Issue: 2 Pages: 162-171
  • DOI: 10.1007/s00392-015-0899-z
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cystatin C-Based eGFR Is a Superior Prognostic Parameter to Creatinine-Based eGFR in Post-Endovascular Therapy Peripheral Artery Disease Patients (2015)
  • Author(s): Yoichiro Otaki, Hiroki Takahashi, Tetsu Watanabe, Gensai Yamaura, Akira Funayama, Takanori Arimoto, Tetsuro Shishido, Takuya Miyamoto, Isao Kubota.
  • Journal Title: Circulation Journal Volume: 79 Issue: 11 Pages: 2480-2486
  • DOI: 10.1253/circj.CJ-15-0762
  • NAID: 130005104885
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] The HECT-type Ubiquitin E3 ligase ITCH ameliorates left ventricular remodeling and mortality after myocardial infarction (2014)
  • Author(s): Yoichiro Otaki
  • Organizer: 米国心臓病学会
  • Place of Presentation: マコーミックプレイス・コンベンションセンター（アメリカ合衆国）
  • Year and Date: 2014-11-15 – 2014-11-19