Elucidation of regulatory mechanism of cytosolic mitochondrial DNA in cardiac injury and its therapeutic application

• Project/Area Number: 19K22622
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Kyushu University
• Principal Investigator: Tsutsui Hiroyuki 九州大学, 医学研究院, 教授 (70264017)
• Co-Investigator(Kenkyū-buntansha): 松島 将士 九州大学, 大学病院, 助教 (80552869) ; 井手 友美 九州大学, 医学研究院, 准教授 (90380625)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 心不全 / ミトコンドリアDNA / 炎症 / ZBP1 / 心筋障害

Outline of Research at the Start

あらゆる心疾患の終末像である心不全の重症例の生命予後は極めて不良であり、心不全の病態解明と新たな治療戦略の開発は重要な研究課題である。本研究は、『細胞質ミトコンドリアDNA増加によるZBP1の活性化が、炎症、エネルギー代謝異常を引きおこし、心筋リモデリング・心不全の形成・進展に関与する』という仮説を検証するとともにZBP1の安定化による炎症・エネルギー代謝制御というパラダイムに基づく新規心不全治療法の開発を目指すものである。

Outline of Final Research Achievements

In failing hearts and mitochondrial DNA-treated cardiomyocytes, ZBP1 protein levels were increased. ZBP1 knockout mice demonstrated exacerbation of cardiac dysfunction, accompanied by elevation of inflammatory cytokines and NF-kB. In addition, the inhibition of TLR9 decreased ZBP1 protein levels. ZBP1 is positively regulated by TLR9. ZBP1 plays a protective role in cardiac inflammation and injury by negatively regulating NF-kB pathway.

Academic Significance and Societal Importance of the Research Achievements

本研究は心筋細胞における新たな炎症制御機構を明らかにすることで心不全の病態理解を進め、新たな治療法の確立へと発展する可能性がある。

Research Products

• [Journal Article] Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure (2021)
  • Author(s): Furihata T, Takada S, Kakutani N, Maekawa S, Tsuda M, Matsumoto J, Mizushima W, Fukushima A, Yokota T, Enzan N, Matsushima S, Handa H, Fumoto Y, Nio-Kobayashi J, Iwanaga T, Tanaka S, Tsutsui H, Sabe H, Kinugawa S.
  • Journal Title: Commun Biol. Volume: 4 Issue: 1 Pages: 138-138
  • DOI: 10.1038/s42003-021-01675-4
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity (2020)
  • Author(s): Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui
  • Journal Title: JCI insight Volume: 5 Issue: 9
  • DOI: 10.1172/jci.insight.132747
  • Peer Reviewed / Open Access
• [Journal Article] DPP (Dipeptidyl Peptidase)-4 Inhibitor Attenuates Ang II (Angiotensin II)?Induced Cardiac Hypertrophy via GLP (Glucagon-Like Peptide)-1?Dependent Suppression of Nox (Nicotinamide Adenine Dinucleotide Phosphate Oxidase) 4-HDAC (Histone Deacetylase) 4 Pathway (2020)
  • Author(s): Okabe Kosuke、Matsushima Shouji、Ikeda Soichiro、Ikeda Masataka、Ishikita Akihito、Tadokoro Tomonori、Enzan Nobuyuki、Yamamoto Taishi、Sada Masashi、Deguchi Hiroko、Shinohara Keisuke、Ide Tomomi、Tsutsui Hiroyuki
  • Journal Title: Hypertension Volume: 75 Issue: 4 Pages: 991-1001
  • DOI: 10.1161/hypertensionaha.119.14400
  • Peer Reviewed / Open Access
• [Journal Article] Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway. (2019)
  • Author(s): Ikeda S, Matsushima S, Okabe K, Ikeda M, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Sada M, Deguchi H, Morimoto S, Ide T, Tsutsui H
  • Journal Title: Scientific reports Volume: 9 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-019-46367-6
  • Peer Reviewed / Open Access