Novel treatment for heart failure by inflammasome regulation targeting calcium-calmodulin dependent protein kinase II

• Project/Area Number: 20K17119
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamaguchi University
• Principal Investigator: Suetomi Takeshi 山口大学, 医学部附属病院, 助教 (40749842)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: カルモジュリンキナーゼ / 心不全 / 自然炎症 / インフラマソーム / リモデリング / カルモジュリン依存キナーゼ / 線維化 / マクロファージ / HFpEF / 左室拡張能 / 細胞外小胞 / 炎症

Outline of Research at the Start

心不全の治療法は大半が対症療法であり、病態に根本的にアプローチする治療が求められている。最近の臨床試験の結果から、心機能低下に炎症が関与していることが再び注目されている。心負荷に伴う炎症がどのように発生し伝わるのか長らく不明であったが、申請者らの最近の研究により、心筋細胞内のカルシウム・カルモジュリン依存性キナーゼ活性化に伴うインフラマソームの発生が起源となっていることが明らかになった。本研究ではこの知見をさらに発展させ、「心筋細胞におけるインフラマソーム発生」および「他の細胞へのシグナル拡散」を標的とした、新しい心不全治療法の確立を目指す。

Outline of Final Research Achievements

We analyzed changes of caspase-1 activity in cultured cardiomyocytes associated with overexpression or suppression of CaMKII. Extracellular vesicles in the culture medium were also analyzed. Signals originated from myocardial cells induced macrophage responses through mediators such as extracellular vesicles, IL-1β and IL-18. In chronic pressure overload model and HFpEF model, inflammatory responses and fibrosis signals were significantly reduced in macrophage-specific CaMKII knockout mice compared to wild type. Chronic left ventricular myocardial remodeling was also suppressed by CaMKII knockout.

Academic Significance and Societal Importance of the Research Achievements

マクロファージ内CaMKIIδは慢性心負荷に伴う炎症反応、線維化および心機能低下に関与しており、心筋リモデリングにおける治療標的としての有用性が示唆された。マクロファージにおけるCaMKII-インフラマソームシグナル伝達解析を継続し、同部位を標的とすることで、従来の免疫抑制薬と異なる選択的な炎症抑制治療としての心不全治療への臨床応用を目指す。

Research Products

• [Int'l Joint Research] University of California, San Diego(米国)
• [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 / Open Access
• [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] 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] 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 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] 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
• [Presentation] Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II signaling is essential for adverse cardiac remodeling (2022)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: ESC Congress 2021 - European Society of Cardiology
  • Int'l Joint Research
• [Presentation] Anti-inflammatory approach targeting CaMKIIδ as a novel therapeutic strategy to the heart failure (2022)
  • Author(s): Takeshi Suetomi, Masafumi Yano
  • Organizer: The 5th JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II (CaMKII) signaling is essential for adverse cardiac remodeling (2022)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: International Society for Heart Research
  • Int'l Joint Research
• [Presentation] Mediation of inflammation through Ca2+/ Calmodulin-dependent protein kinase II (CaMKII) in macrophage is essential for pressure overload-induced adverse cardiac remodeling (2022)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 日本心不全学会学術集会
• [Presentation] George E. Brown Memorial Lecture: Mediation of inflammation through Ca2+/ Calmodulin-dependent protein kinase II (CaMKII) in macrophage is essential for pressure overload-induced adverse cardiac remodeling (2022)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Sterile Inflammation through Ca2+/ Calmodulin-Dependent Protein Kinase II is Essential for Adverse Cardiac Remodeling (2021)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Michiaki Kono, Toshiro Kajii, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano.
  • Organizer: The 85th Annual Scientific Meeting of the Japanese Circulation Society (JCS2021)
• [Presentation] Anti-inflammatory approach targeting CaMKIIδ as a novel therapeutic strategy to the heart failure (2021)
  • Author(s): Takeshi Suetomi, Masafumi Yano
  • Organizer: The 5th JCS Council Forum on Basic CardioVascular Research
• [Presentation] Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II signaling is essential for adverse cardiac remodeling (2021)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: European Society of Cardiology Congress 2021
  • Int'l Joint Research
• [Presentation] Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II (CaMKII) signaling is essential for adverse cardiac remodeling (2021)
  • Author(s): Takeshi Suetomi, Shinichi Okuda, Yoko Okamoto, Satomi Tateda, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: the 38th Annual Scientific Meeting of the Japanese Section of the International Society for Heart Research (ISHR)
  • Int'l Joint Research
• [Presentation] Sterile Inflammation through CaMKII Signaling in non-ischemic heart failure (2020)
  • Author(s): Takeshi Suetomi
  • Organizer: The 4th JCS Council Forum on Basic CardioVascular Research
• [Presentation] Anti-inflammatory approach for heart failure targeting Calcium-Calmodulin dependent protein kinase (2020)
  • Author(s): Takeshi Suetomi
  • Organizer: The 84th Annual Scientific Meeting of the Japanese Circulation Society (JCS2020)
• [Book] Medical Science Digest 2022年10月号 予防を科学する：炎症細胞社会学 The Science of Prevention: Inflammatory Cell Sociology (2022)
  • Author(s): 末冨 建ほか
  • Total Pages: 55
  • Publisher: 北隆館ニューサイエンス社