The investigation of functional role of CCR4-NOT compex in pathorogical cardiac remodeling

• Project/Area Number: 18K15879
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Akita University
• Principal Investigator: SATO TERUKI 秋田大学, 医学部附属病院, 助教 (30733422)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CCR4-NOT複合体 / 心不全 / 心臓リモデリング

Outline of Final Research Achievements

We investigated the functional role of CCR4-NOT deadenylase in pathological cardiac remodeling. Since protein X, a key factor of deadenylase, was upregulated in pressure overload-induced cardiac hypertrophy, we analyzed heart function of protein X KO mice which showed cardiac dysfunction and hypertrophy. RNA sequence revealed upregulation of inflammatory, cardiac hypertrophy and fibrosis associated genes. We thus focused on geneY, and generated protein X; gene Y double KO mice. Gene Y deficiency rescued cardiac dysfunction and hypertrophy of X KO mice with pressure overload. These results implicate that CCR4-NOT deadenylase negatively regulates cardiac remodeling induced by pressure overload via shortening of poly(A)tail of target mRNA.

Academic Significance and Societal Importance of the Research Achievements

心不全パンデミックと称されるように、今後心不全患者が増加することが予想されている。
有効な薬物療法やデバイス治療が開発されてきた一方で、いまだに心不全の予後は不良であるが、そこには心不全発症の分子病態解明が不十分であることから新規治療方法の開発が進まない背景がある。本研究では、RNA代謝制御に着目して、心臓リモデリングの病態解明を目的とした解析を行った。CCR4-NOT複合体は巨大なタンパク質複合体であり、生命維持に必須であることが分かっている。その機能的意義を解明することで、新たな心不全発症機序の解明やひいては治療法開発に貢献すると考えられる。

Research Products

• [Journal Article] B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction (2020)
  • Author(s): Minato T, Nirasawa S, Sato T, Yamaguchi T, Hoshizaki M, Inagaki T, Nakahara K, Yoshihashi T, Ozawa R, Yokota S, Natsui M, Koyota S, Yoshiya T, Yoshizawa-Kumagaye K, Motoyama S, Gotoh T, Nakaoka Y, Penninger JM, Watanabe H, Imai Y, Takahashi S, Kuba K
  • Journal Title: Nature Communications Volume: 11(1) Issue: 1 Pages: 1058-1058
  • DOI: 10.1038/s41467-020-14867-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The functional role of endogenous APJ agonists; Apelin and Elabela/Toddler in cardiovascular diseases (2019)
  • Author(s): Sato Teruki、Kuba Keiji
  • Journal Title: Folia Pharmacologica Japonica Volume: 153 Issue: 4 Pages: 172-178
  • DOI: 10.1254/fpj.153.172
  • NAID: 130007630616
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of arterial wall vascularization using superb microvascular imaging in active-stage Takayasu arteritis. (2019)
  • Author(s): Sato W, Sato T, Iino T, Seki K, Watanabe H
  • Journal Title: Eur Heart J Cardiovasc Imaging. Volume: 20 Issue: 6 Pages: 719-719
  • DOI: 10.1093/ehjci/jey285
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling (2019)
  • Author(s): Sato Teruki、Kadowaki Ayumi、Suzuki Takashi、Ito Hiroshi、Watanabe Hiroyuki、Imai Yumiko、Kuba Keiji
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 2 Pages: 239-239
  • DOI: 10.3390/ijms20020239
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. (2018)
  • Author(s): Kuba K, Sato T, Imai Y, Yamaguchi T
  • Journal Title: Peptides. Volume: in press Pages: 62-70
  • DOI: 10.1016/j.peptides.2018.04.011
  • Peer Reviewed / Open Access
• [Journal Article] The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function (2018)
  • Author(s): Yamaguchi Tomokazu et al
  • Journal Title: Science Signaling Volume: 11 Issue: 516 Pages: 3638-3638
  • DOI: 10.1126/scisignal.aan3638
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 心不全病態におけるAPJ受容体リガンド(Apelin/Elabela)の機能的意義の解明 (2019)
  • Author(s): 佐藤輝紀
  • Organizer: 心脈管作動物質学会
• [Presentation] Loss of endogenous Apelin augments Angiotensin II-mediated cardiac remodeling (2019)
  • Author(s): 佐藤輝紀
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] A novel APJ ligand, ELABELA, protects from pathological cardiac remodeling induced by pressure overload and Angiotensin II (2018)
  • Author(s): Teruki Sato, Hiroyuki Watanabe, Akinori Kimura, Hiroshi Ito, Yumiko Imai,Keiji Kuba
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] 新規心血管病治療標的としてのApelin/ELABELA -APJ受容体システム (2018)
  • Author(s): 佐藤輝紀、久場敬司
  • Organizer: 第69回日本薬理学会北部会
• [Presentation] ELABELA, a novel APJ ligand, protects against pressure overload or Angiotensin II-induced cardiac remodeling. (2018)
  • Author(s): Teruki Sato, Hiroyuki Watanabe,Tomokazu Yamaguchi,Hiroshi Ito, Keiji Kuba
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] Endogenous Apelin supresses Angiotensin II-induced Cardiac hypertrophy and fibrosis (2018)
  • Author(s): Teruki Sato, Hiroyuki Watanabe,Ayumi Kadowaki, Keiji Kuba
  • Organizer: 第22回日本心不全学会学術集会