カルモジュリンの核内移行制御による新しい心不全・心肥大の治療

• Project/Area Number: 21K08054
• 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: Yamaguchi University
• Principal Investigator: 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122)
• Co-Investigator(Kenkyū-buntansha): 小田 哲郎 山口大学, 医学部附属病院, 講師 (40569290)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: リアノジン受容体 / カルモジュリン / 心肥大 / ryanodine receptor / calmodulin / herpud1 / NFAT / Herpud1 / 心筋細胞

Outline of Research at the Start

本研究は、心筋のリアノジン受容体(RyR2)結合カルモジュリン(CaM)が、心不全、心肥大の進行に関するkey分子となることを証明し、心不全、心肥大に対する、これまでに無い治療法を確立することである。RyR2結合CaMはRyR2のCa放出の重要な調節因子であるばかりでなく、心筋細胞におけるCaMの供給源となり、CaMKIIやCaNの活性化を介して、心肥大、心不全に重要なシグナル伝達に関与していることがわかった。本研究では申請者の仮説を証明し、これまでに無い治療法を確立する。

Outline of Annual Research Achievements

本研究は、心筋のリアノジン受容体(RyR2)結合カルモジュリン(CaM)が、心不全、心肥大の進行に関するkey分子となることを証明し、心不全、心肥大に対する、これまでに無い治療法を確立することである。
1)RyR2からのcalmodulin(CaM)解離抑制による肥大制御
申請者はRyR2のCaM結合ドメイン(CaMBD)に１アミノ酸変異を組み込んだ変異ペプチドを多数スクリーニングした結果CaMの結合親和性が著しく高まるアミノ酸変異を発見した。この知見をもとに、RyR2上のCaM結合ドメイン内で１アミノ酸のみを変異させることによりCaMの結合親和性が格段に高まる変異を組み込んだknock-in (KI)マウス: (RyR2 V3599K KIマウス)を作成することに成功した。このマウスを7%の低酸素下で飼育したところ、WTマウスでは明らかに心肥大、心筋細胞肥大を生じたにもかかわらず。RyR2 V3599K KIマウスではまったく肥大を生じなかった。
2)ラット心筋由来のH９C２細胞において、Ang IIは，CaMの核内移行および細胞質Ca2+の上昇を伴って，H9C2細胞の肥大を誘発したが、RyR2を安定化させ、CaMの解離を抑制するダントロレンの添加はCaMの核内移行および細胞質Ca2+の上昇を阻害し，Ang II誘発肥大を抑制した。一方で、Herpud1の過剰発現は，CaMの核内移行および細胞質Ca2+の上昇を妨げることなく，Ang IIによる細胞肥大を抑制した。

Research Products

• [Journal Article] Effects of pemafibrate on left ventricular diastolic function in patients with type 2 diabetes mellitus: a pilot study (2023)
  • Author(s): Yamamoto Kaoru、Ohta Yasuharu、Taguchi Akihiko、Akiyama Masaru、Nakabayashi Hiroko、Nagao Yuko、Ryoko Hatanaka、Wada Yasuaki、Yamamoto Takeshi、Yano Masafumi、Tanizawa Yukio
  • Journal Title: Diabetology International Volume: 14 Issue: 4 Pages: 434-439
  • DOI: 10.1007/s13340-023-00645-x
  • Peer Reviewed / Open Access
• [Journal Article] RyR2-stabilization therapy with dantrolene against left ventricular remodeling and lethal arrhythmia in heart failure (2023)
  • Author(s): Kobayashi Shigeki、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 182 Pages: 25-27
  • DOI: 10.1016/j.yjmcc.2023.07.002
  • Peer Reviewed
• [Journal Article] The impact of geriatric nutritional risk index on one-year outcomes in hospitalized elderly patients with heart failure (2023)
  • Author(s): Miura Masakazu、Okuda Shinichi、Murata Kazuhiro、Ohno Yutaka、Katou Satoshi、Nakao Fumiaki、Ueyama Takeshi、Yamamoto Takeshi、Ikeda Yasuhiro
  • Journal Title: Frontiers in Cardiovascular Medicine Volume: 10 Pages: 1190548-1190548
  • DOI: 10.3389/fcvm.2023.1190548
  • Peer Reviewed
• [Journal Article] RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure (2023)
  • Author(s): Fujii Shohei、Kobayashi Shigeki、Chang Yaowei、Nawata Junya、Yoshitomi Ryosuke、Tanaka Shinji、Kohno Michiaki、Nakamura Yoshihide、Ishiguchi Hironori、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Okuda Shinichi、Okamura Takayuki、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 178 Pages: 36-50
  • DOI: 10.1016/j.yjmcc.2023.03.007
  • Peer Reviewed
• [Journal Article] Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats (2023)
  • Author(s): Nawata Junya、Yamamoto Takeshi、Tanaka Shinji、Yano Yasutake、Uchida Tomoyuki、Fujii Shohei、Nakamura Yoshihide、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 34 Pages: 101449-101449
  • DOI: 10.1016/j.bbrep.2023.101449
  • Peer Reviewed / Open Access
• [Journal Article] Herpud1 modulates hypertrophic signals independently of calmodulin nuclear translocation in rat myocardium-derived H9C2 cells (2023)
  • Author(s): Fujioka Riko、Yamamoto Takeshi、Maruta Akihiro、Nakamura Yoshihide、Tominaga Naoomi、Inamitsu Masako、Oda Tetsuro、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 652 Pages: 61-67
  • DOI: 10.1016/j.bbrc.2023.02.038
  • Peer Reviewed
• [Journal Article] Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice (2023)
  • Author(s): Yano Yasutake、Kobayashi Shigeki、Uchida Tomoyuki、Chang Yaowei、Nawata Junya、Fujii Shohei、Nakamura Yoshihide、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 642 Pages: 175-184
  • DOI: 10.1016/j.bbrc.2022.12.063
  • Peer Reviewed / Open Access
• [Journal Article] Stabilizing Tetrameric Structure of Ryanodine Receptor Cures Lethal Arrhythmia in Heart Failure (2022)
  • Author(s): Kobayashi Shigeki、Yamamoto Takeshi、Yoshiga Yasuhiro、Okamura Takayuki、Kawano Reo、Yano Masafumi
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 15 Issue: 10 Pages: 714-717
  • DOI: 10.1161/circep.122.011220
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells (2022)
  • Author(s): Uchida Tomoyuki、Oda Tetsuro、Yamamoto Takeshi、Inamitsu Masako、Sakai Chihiro、Uchinoumi Hitoshi、Suetomi Takeshi、Nakamura Yoshihide、Okamoto Yoko、Tateda Satomi、Fujii Shohei、Tanaka Shinji、Nawata Junya、Okamura Takayuki、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 628 Pages: 155-162
  • DOI: 10.1016/j.bbrc.2022.08.069
  • Peer Reviewed / Open Access
• [Journal Article] Dantrolene, a stabilizer of the ryanodine receptor, prevents collagen-induced arthritis. (2022)
  • Author(s): 58)Nawata T, Sakai H, Honda T, Otsuka M, Fujita H, Uchinoumi H, Kobayashi S, Yamamoto T, Asagiri M, Yano M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 624 Pages: 141-145
  • DOI: 10.1016/j.bbrc.2022.07.111
  • Peer Reviewed / Open Access
• [Journal Article] Dantrolene reduces platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and neointimal formation following vascular injury in mice (2022)
  • Author(s): Sakai Chihiro、Mikawa Mei、Yamamoto Takeshi、Uchida Tomoyuki、Nakamura Yoshihide、Akase Hideaki、Suetomi Takeshi、Tominaga Naoomi、Inamitsu Masako、Oda Tetsuro、Okamura Takayuki、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 623 Pages: 51-58
  • DOI: 10.1016/j.bbrc.2022.07.038
  • Peer Reviewed / Open Access
• [Journal Article] Herpud1 suppress angiotensin II induced hypertrophy in cardiomyocytes. (2022)
  • Author(s): Mikawa M, Sakai C, Yamamoto T, Nakamura Y, Tanaka S, Tominaga N, Inamitsu M, Oda T, Kobayashi S, Yano M.
  • Journal Title: Biochem Biophys Rep. Volume: 30 Pages: 101248-101248
  • DOI: 10.1016/j.bbrep.2022.101248
  • Peer Reviewed / Open Access
• [Journal Article] Stabilization of RyR2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension. (2022)
  • Author(s): Tanaka S, Yamamoto T, Mikawa M, Nawata J, Fujii S, Nakamura Y, Kato T, Fukuda M, Suetomi T, Uchinoumi H, Oda T, Okuda S, Okamura T, Kobayashi S, Yano M.
  • Journal Title: Heart Rhythm. Volume: S1547 Issue: 6 Pages: 00119-00119
  • DOI: 10.1016/j.hrthm.2022.02.003
  • Peer Reviewed / Open Access
• [Journal Article] Low-cost and High-Precision Stepping Motor Controlled Multi-Point Automatic Time-Lapse Microscope. (2021)
  • Author(s): Maruta A, Sakai C, Mikawa M, Akita H, Inamitsu M, Fujioka R, Saiki Y, Yamamoto T
  • Journal Title: the Bulletin of the Yamaguchi Medical School Volume: 68 Pages: 41-47
  • NAID: 120007178346
  • Peer Reviewed / Open Access
• [Journal Article] Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease (2021)
  • Author(s): Nakamura Yoshihide、Yamamoto Takeshi、Xu Xiaojuan、Kobayashi Shigeki、Tanaka Shinji、Tamitani Masaki、Saito Takashi、Saido Takaomi C.、Yano Masafumi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 7289-7289
  • DOI: 10.1038/s41598-021-86822-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] リアノジン受容体安定化治療が心筋梗塞後の左室リモデリングや心室頻拍を抑制する (2023)
  • Author(s): 藤井翔平、小林茂樹、矢野泰健、内田智之、常 耀偉、縄田純也、中村吉秀、 末冨 建、内海仁志、小田哲郎、岡村誉之、山本 健、矢野雅文
  • Organizer: 第9回日本心筋症研究会
• [Presentation] 心筋型リアノジン受容体 4 量体構造の安定化は心筋梗塞後の予後を改善する (2023)
  • Author(s): 藤井翔平、小林茂樹、矢野泰健、内田智之、常 耀偉、中村吉秀、末冨 建、 内海仁志、小田哲郎、岡村誉之、山本 健、矢野雅文
  • Organizer: 第122回日本循環器学会中国四国合同地方会
• [Presentation] Stabilization of RyR2 maintains right ventricular function, and improves prognosis in pulmonary hypertension (2021)
  • Author(s): Shinji Tanaka, Takeshi Yamamoto, Junya Nawata, Shohei Fujii, Yoshihide Nakamura, Michiaki Kohno, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会
• [Presentation] The role of Herpud1 as a anti-hypertrophic gene in cardiomyocytes (2021)
  • Author(s): Mei Mikawa, Takeshi Yamamoto, Chizuru Sakai, Riko Fujioka, Akihiro Maruta, Yoshihide Nakamura, Masako Inamitsu, Naoomi Tominaga, Masahumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会