Molecular mechanisms of cell proliferation of adult mammalian cardiomyocytes

• Project/Area Number: 18H02603
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Osaka University
• Principal Investigator: Fujio Yasushi 大阪大学, 薬学研究科, 教授 (20359839)
• Co-Investigator(Kenkyū-buntansha): 尾花 理徳 大阪大学, 薬学研究科, 准教授 (50745883) ; 前田 真貴子 大阪大学, 薬学研究科, 准教授 (70461168) ; 中山 博之 大阪大学, 薬学研究科, 准教授 (40581062)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 心筋細胞増殖 / 心筋再生 / 心筋組織修復 / 心筋炎 / 心不全 / 再生治療 / 治療標的

Outline of Final Research Achievements

To develop a novel heart regenerative therapy that promotes the proliferation of endogenous cardiomyocytes, we have been investigating the signaling pathways responsible cardiomyocyte proliferation. As a result, we found that YAP, which determines the organ size, enhances the proliferative activity of adult mammalian cardiomyocytes under the pathological conditions. Furthermore, we performed chemical library screening and identified 5 chemicals that increased the number of proliferating cardiomyocytes.

Academic Significance and Societal Importance of the Research Achievements

哺乳類の心筋細胞は、生直後に増殖能を著しく失うことから、成体の心臓は再生能が低い臓器である。そのため、様々な循環器疾患により心筋細胞死が誘発されても、多くの場合心筋細胞は増殖するにいたらず、心筋細胞数が減少し、その結果、心不全が発症する。本研究の成果は、内因性の心筋細胞を増殖させる技術の開発につながる可能性がある。その技術を使うことで、循環器疾患によって減少した心筋細胞を、内因性の心筋細胞を増殖させることにより回復させることができるようになり、心不全の発症を抑制できるかもしれない。

Research Products

• [Journal Article] Title: Gene Transfer by Pyro-Drive Jet Injector is a Novel Therapeutic Approach for Muscle Diseases (2021)
  • Author(s): Nakae Takafumi、Obana Masanori、Maeda Takahiro、Ikeda Akari、Miyazaki Hiroshi、Tanaka Shota、Maeda Makiko、Yamashita Kunihiko、Terai Kazuhiro、Obika Satoshi、Fujio Yasushi
  • Journal Title: Gene Volume: in press Pages: 145664-145664
  • DOI: 10.1016/j.gene.2021.145664
  • Peer Reviewed / Open Access
• [Journal Article] Adenovirus Vector?Induced IL-6 Promotes Leaky Adenoviral Gene Expression, Leading to Acute Hepatotoxicity (2020)
  • Author(s): Shimizu Kahori、Sakurai Fuminori、Iizuka Shunsuke、Ono Ryosuke、Tsukamoto Tomohito、Nishimae Fumitaka、Nakamura Shin-ichiro、Nishinaka Toru、Terada Tomoyuki、Fujio Yasushi、Mizuguchi Hiroyuki
  • Journal Title: The Journal of Immunology Volume: 206 Issue: 2 Pages: 410-421
  • DOI: 10.4049/jimmunol.2000830
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor old astrocyte specifically induced substance is a novel regulator of kidney fibrosis (2020)
  • Author(s): Yamamoto Ayaha、Morioki Hitomi、Nakae Takafumi、Miyake Yoshiaki、Harada Takeo、Noda Shunsuke、Mitsuoka Sayuri、Matsumoto Kotaro、Tomimatsu Masashi、Kanemoto Soshi、Tanaka Shota、Maeda Makiko、Conway Simon J.、Imaizumi Kazunori、Fujio Yasushi、Obana Masanori
  • Journal Title: The FASEB Journal Volume: 35 Issue: 2
  • DOI: 10.1096/fj.202001820r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β2‐adrenergic stimulation induces interleukin‐6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts (2020)
  • Author(s): Tanaka Shota、Imaeda Atsuki、Matsumoto Kotaro、Maeda Makiko、Obana Masanori、Fujio Yasushi
  • Journal Title: Pharmacology Research & Perspectives Volume: 8 Issue: 2
  • DOI: 10.1002/prp2.590
  • Peer Reviewed / Open Access
• [Journal Article] QT/QTc study shows that a novel 5-HT4 receptor partial agonist minesapride has no effect on QT prolongation. (2020)
  • Author(s): Hamatani, T., Noda, N., Takagaki, T., Yodo, Y., Kakuyama, H., Kaji, Y., Fujio, Y.
  • Journal Title: Clin. Pharmacol. Drug Develop Volume: in press Issue: 8 Pages: 938-951
  • DOI: 10.1002/cpdd.778
  • Peer Reviewed
• [Journal Article] Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells (2020)
  • Author(s): Lin Y, Higashisaka K, Shintani T, Maki A, Hanamuro S, Haga Y, Maeda S, Tsujino H, Nagano K, Fujio Y, Tsutsumi Y
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4748-4748
  • DOI: 10.1038/s41598-020-61727-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Old-Age Onset Progressive Cardiac Contractile Dysfunction in a Patient with Polycystic Kidney Disease Harboring a <i>PKD1</i> Frameshift Mutation (2019)
  • Author(s): Suwa Yoshinobu、Higo Shuichiro、Nakamoto Kei、Sera Fusako、Kunimatsu Suzuka、Masumura Yuki、Kanzaki Machiko、Mizote Isamu、Mizuno Hiroya、Fujio Yasushi、Hikoso Shungo、Sakata Yasushi
  • Journal Title: International Heart Journal Volume: 60 Issue: 1 Pages: 220-225
  • DOI: 10.1536/ihj.18-184
  • NAID: 130007557187
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-01-31
  • Peer Reviewed / Open Access
• [Journal Article] The CalcR-PKA-Yap1 Axis Is Critical for Maintaining Quiescence in Muscle Stem Cells. (2019)
  • Author(s): Zhang L, Noguchi YT, Nakayama H, Kaji T, Tsujikawa K, Ikemoto-Uezumi M, Uezumi A, Okada Y, Doi T, Watanabe S, Braun T, Fujio Y, Fukada SI.
  • Journal Title: Cell Rep Volume: 19 Issue: 8 Pages: 2154-63
  • DOI: 10.1016/j.celrep.2019.10.057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodeling after myocardial infarction (2019)
  • Author(s): Matsumoto, K., Obana, M., Kobayashi, A., Miyagawa, S., Maeda, M., Sakata, Y., Nakayama, H., Sawa, Y., Fujio, Y.
  • Journal Title: Cardiovasc. Res. Volume: 115 Issue: 4 Pages: 765-775
  • DOI: 10.1093/cvr/cvy254
  • Peer Reviewed / Open Access
• [Journal Article] Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice. (2019)
  • Author(s): 1.Imaeda A, Tanaka S, Tonegawa K, Fuchigami S, Obana M, Maeda M, Kihara M, Kiyonari H, Conway SJ, Fujio Y, Nakayama H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 510 Issue: 1 Pages: 149-155
  • DOI: 10.1016/j.bbrc.2019.01.070
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation (2018)
  • Author(s): Shirakura Keisuke、Ishiba Ryosuke、Kashio Taito、Funatsu Risa、Tanaka Toru、Fukada So-ichiro、Ishimoto Kenji、Hino Nobumasa、Kondoh Masuo、Ago Yukio、Fujio Yasushi、Yano Kiichiro、Doi Takefumi、Aird William C.、Okada Yoshiaki
  • Journal Title: Journal of Cell Science Volume: 132 Pages: 220228-220228
  • DOI: 10.1242/jcs.220228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caveolae-specific CaMKII signaling in the regulation of voltage-dependent calcium channel and cardiac hypertrophy. (2018)
  • Author(s): Tanaka, S., Fujio, Y., Nakayama, H.
  • Journal Title: Front. Physiol. Volume: 9 Pages: 1081-1081
  • DOI: 10.3389/fphys.2018.01081
  • Peer Reviewed / Open Access
• [Journal Article] Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer. (2018)
  • Author(s): Shintani, T., Higashisaka, K., Maeda, M., Hamada, M., Tsuji, R., Kurihara, K., Kashiwagi, Y., Sato, A., Obana, M., Yamamoto, A., Kawasaki, K., Lin, Y., Kijima, T., Kinehara, Y., Miwa, Y., Maeda, S., Morii, E., Kumanogoh, A., Tsutsumi, Y., Nagatomo, I., Fujio, Y.
  • Journal Title: Oncotarget Volume: 9 Issue: 101 Pages: 37520-37533
  • DOI: 10.18632/oncotarget.26494
  • Peer Reviewed / Open Access
• [Presentation] Activation of YAP is essential for the myocardial recovery from myocarditis (2021)
  • Author(s): 福山尚希、亀谷祐介、和田祐理子、鈴木翔大、梅田綾香、前田真貴子、田中翔大、尾花理徳、藤尾 慈
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Cardioprotective roles of novel cell death inhibitor, defender against cell death 1 (Dad1) (2021)
  • Author(s): 森 翔太、田中翔大、前田真貴子、尾花理徳、藤尾 慈
  • Organizer: 第94回日本薬理学会年会
• [Presentation] CXCL10 is an anti-angiogenic factor downstream of p53 in cardiomyocytes (2021)
  • Author(s): 五十嵐竜太、冨松聖史、前田真貴子、田中翔大、尾花理徳、藤尾 慈
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Molecular mechanisms of myocardial reverse remodeling after myocarditis (2020)
  • Author(s): Yasushi Fujio
  • Organizer: Basic Cardiovascular Science 2020 Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Adult murine cardiomyocytes exhibit reparative/regenerative activities in the healing process of myocarditis. (2020)
  • Author(s): Fujio, Y., Miyawaki, A., Matsumoto, K., Tanaka, S., Maeda, M., Obana, M.
  • Organizer: 4th Annual 2020 International Hawaii Cardiovascular Symposium
  • Int'l Joint Research / Invited
• [Presentation] 細胞死が惹起する心筋炎症と組織修復：新たな心不全治療を目指して (2020)
  • Author(s): 藤尾 慈、宮脇昭光、尾花理徳、松本浩太朗、前田真貴子
  • Organizer: 日本薬学会第140年会
  • Invited
• [Presentation] 哺乳類心筋細胞の細胞周期活性誘導化合物のスクリーニング系の構築 (2020)
  • Author(s): 松井 理紗、福山 尚希、亀谷 祐介、和田 祐理子、松本 浩太朗、前田 真貴子、尾花 理徳、藤尾 慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 転写因子OASISの阻害は腎線維化を抑制する (2020)
  • Author(s): 山本彩葉、尾花理徳、中江崇文、三宅芳明、光岡小百合、前田真貴子、今泉和則、松本浩太朗、藤尾慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 心線維芽細胞β2アドレナリン受容体シグナルはパラクラインを介して心臓の肥大を惹起する (2020)
  • Author(s): 今枝 厚貴、田中 翔大、松本 浩太朗、前田 真貴子、尾花 理徳、藤尾 慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 炎症抑制脂質分子Maresin １は新生児ラット培養心筋細胞において生理的肥大を惹起する (2020)
  • Author(s): 小林亜里沙、トリワヒュニ、五十嵐竜太、冨松聖史、松本浩太朗、前田真貴子、尾花理徳、藤尾慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Dad1は細胞接着の障害によって誘導される心筋細胞死を抑制する (2020)
  • Author(s): 森 翔太, 木村 瑠美, 渕上 翔太, 松本 浩太朗, 前田 真貴子, 尾花 理徳, 藤尾 慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] アドレナリンβ2受容体刺激はｃＡＭＰ/PKA/CREB経路を介したArid5a発現誘導によりIL-6の産生を亢進させる (2020)
  • Author(s): 田中翔大、今枝厚貴、松本浩太朗、前田真貴子、尾花理徳、藤尾慈
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Runx2発現ミエロイド細胞は梗塞後心筋リモデリングを抑制する新規心保護サブセットである (2019)
  • Author(s): 松本浩太朗、芦塚萌、熊谷渉平、奥崎大介、尾花理徳、前田真貴子、中山博之、藤尾 慈
  • Organizer: 日本薬理学会92回年会
• [Presentation] ポドサイトにおけるOASISの発現抑制は糖尿病による腎機能の悪化を抑制する (2019)
  • Author(s): 4.三宅芳明、尾花威徳、山本彩葉、野田竣介、金本聡自、前田真貴子、淺沼克彦、今泉和則、中山博之、藤尾慈
  • Organizer: 日本薬理学会92回年会
• [Presentation] 成体マウスにおける単核心筋細胞の特性解析 (2019)
  • Author(s): 中安佑介、松井理紗、福山尚希、亀谷祐介、和田祐理子、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 日本薬理学会92回年会
• [Presentation] CGRRF1の過剰発現は培養心筋細胞の肥大を誘導する (2019)
  • Author(s): 木下真希、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 日本薬理学会92回年会
• [Presentation] Blockade of NKG2D / NKG2D ligands interaction as a novel therapeutic strategy against heart failure (2018)
  • Author(s): Matsumoto. K., Obana. M., Maeda. M., Nakayama. H.,Fujio. Y.
  • Organizer: 18th World Congress of Basic And Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Pharmacogenomics-Based Prediction of Warfarin Maintenance Dose Overrides Racial Differences (2018)
  • Author(s): Sasano, M.,Maeda, M.,Ohno, M.,Fukuda, Y.,Yokoyama, J.,Maeda, S.,Miyagawa, S.,Sawa, Y.,Fujio,Y.
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] Blockade of NKG2D / NKG2D Ligand Interaction Attenuated Post-Infarct Myocardial Injury. (2018)
  • Author(s): Matsumoto, K., Obana, M., Kobayashi, A.,Kihara, M.,Shioi, G., Miyagawa, S., Maeda, M.,Sakata,Y., Nakayama, H., Sawa, Y.,Fujio, Y.
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Remarks] 大阪大学大学院薬学研究科・薬学部
  • URL: http://www.phs.osaka-u.ac.jp/
• [Remarks] 臨床薬効解析学分野
  • URL: http://www.phs.osaka-u.ac.jp/homepage/b014/