Development of novel therapeutic strategy for ischemic heart diseases through targeting protein degradation

• Project/Area Number: 17K09577
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: Kato Hisakazu 大阪大学, 医学系研究科, 助教 (30589312)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 虚血性心疾患 / ATP / ミトコンドリア / タンパク質分解 / 薬剤スクリーニング / 心不全 / スクリーニング / 分子心臓学

Outline of Final Research Achievements

In this study, with the aim of developing a novel therapeutic strategy for ischemic heart disease that directly enhances mitochondrial ATP production, we identified compounds that inhibit the degradation of the ATP-synthesis regulator G0S2 using originally constructed screening system. These compounds enhanced ATP production in cardiomyocytes and showed a remarkable cytoprotective effect. By further utilizing this screening system, we identified a novel E3 ligase involved in G0S2 degradation and clarified a novel mechanism of G0S2 degradation. In the future, we plan to address the mechanism of inhibiting G0S2 degradation by these compounds and to administer it to the heart failure model mice.

Academic Significance and Societal Importance of the Research Achievements

心臓は持続的な収縮弛緩の繰り返しによって莫大なエネルギー（ATP）を消費する。そのため狭心症などで、ATPの需要と供給のバランスが崩れると、容易に心不全となりうる。循環器領域で幾つかの分子標的治療が進められているが、虚血性疾患を標的としたものは未だ開発されておらず、直接的にATP産生を増強させる治療法の開発が望まれている。本研究で明らかにしたATP産生制御因子G0S2の分解を阻害する化合物は、直接的に心筋細胞のATPを増産できる点において、画期的な虚血性心疾患の治療法につながることが期待される。

Research Products

• [Journal Article] In vivo real‐time ATP imaging in zebrafish hearts reveals G0s2 induces ischemic tolerance (2020)
  • Author(s): Kioka Hidetaka、Kato Hisakazu、Fujita Takeshi、Asano Yoshihiro、Shintani Yasunori、Yamazaki Satoru、Tsukamoto Osamu、Imamura Hiromi、Kogo Mikihiko、Kitakaze Masafumi、Sakata Yasushi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 2 Pages: 2041-2054
  • DOI: 10.1096/fj.201901686r
  • Peer Reviewed
• [Journal Article] Higd1a improves respiratory function in the models of mitochondrial disorder (2019)
  • Author(s): Nagao Takemasa、Shintani Yasunori、Hayashi Takaharu、Kioka Hidetaka、Kato Hisakazu、Nishida Yuya、Yamazaki Satoru、Tsukamoto Osamu、Yashirogi Shohei、Yazawa Issei、Asano Yoshihiro、Shinzawa‐Itoh Kyoko、Imamura Hiromi、Suzuki Takeo、Suzuki Tsutomu、Goto Yu‐ichi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 1859-1871
  • DOI: 10.1096/fj.201800389r
  • Peer Reviewed
• [Journal Article] A molecular triage process mediated by RING finger protein 126 and BCL2-associated athanogene 6 regulates degradation of G0/G1 switch gene 2 (2019)
  • Author(s): Kamikubo Kenta、Kato Hisakazu、Kioka Hidetaka、Yamazaki Satoru、Tsukamoto Osamu、Nishida Yuya、Asano Yoshihiro、Imamura Hiromi、Kawahara Hiroyuki、Shintani Yasunori、Takashima Seiji
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 40 Pages: 14562-14573
  • DOI: 10.1074/jbc.ra119.008544
  • Peer Reviewed
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] G0s2 is degraded by RNF126 through the interaction with BAG6-mediated molecular triage process. (2019)
  • Author(s): Kenta Kamikubo, Hisakazu Kato, Seiji Takashima.
  • Organizer: Cold Spring Harbor Laboratory Meeting-Ubiquitin, Autophagy&Disease
  • Int'l Joint Research
• [Presentation] ミトコンドリアATP産生制御因子G0s2を特異的に分解する新規E3 ligaseの同定と機能解析 (2018)
  • Author(s): 神窪謙太、加藤久和、高島成二
  • Organizer: 第91回日本生化学会大会
• [Presentation] ミトコンドリアATP産生制御因子G0s2を特異的に分解するE3複合体の同定と機能解析 (2018)
  • Author(s): 神窪謙太、加藤久和、高島成二
  • Organizer: 1.第41回日本分子生物学会年会
• [Presentation] G0S2を分子標的とした新規ATP合成酵素活性化剤の開発 (2018)
  • Author(s): 加藤 久和
  • Organizer: 創薬シーズ事業化コンペティション
  • Invited
• [Presentation] ミトコンドリアATP産生を制御因子G0s2の量的制御に関する機能解析 (2017)
  • Author(s): 神窪謙太、加藤久和、高島成二
  • Organizer: 第64回 日本生化学会 近畿支部例会
• [Presentation] ミトコンドリアATP産生制御因子G0s2タンパク質を特異的に分解する新規ユビキチンリガーゼの探索 (2017)
  • Author(s): 神窪謙太、加藤久和、高島成二
  • Organizer: ConBio2017
• [Remarks] 大阪大学大学院医学系研究科・生命機能研究科 医化学講座
  • URL: http://medbio.sakura.ne.jp/
• [Funded Workshop] Cold Spring Harbor Laboratory Meeting-Ubiquitin, Autophagy&Disease (2019)