Study of Cardioprotective Signal through STAT3/Pim Kinase

• Project/Area Number: 15K08232
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Osaka University
• Principal Investigator: Makiko Maeda 大阪大学, 薬学研究科, 准教授 (70461168)
• Co-Investigator(Kenkyū-buntansha): 藤尾 慈 大阪大学, 薬学研究科, 教授 (20359839)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 虚血性心疾患 / 心筋保護シグナル / Pim-1キナーゼ / 心筋細胞 / STAT3 / N-cadherin / Il-6ファミリーサイトカイン / Pim-1

Outline of Final Research Achievements

Cardioprotective effect is known to be very important to maintain cardiac homeostasis. Silvestrol, a naturally occurring member of the flavagline family of compounds, inhibits cap-dependent translation by targeting eIF4A, and it is known to decrease the expression of cancer genes. It is also reported that eIF4 family has cell protective effects and eIF4B, exhibits various kinds of biological functions. In cancer cells, eIF4B is activated by Pim-1 kinase. However, pathophysiological roles of Pim-1/eIF4B remain to be elucidated in cardiomyocytes.
In this study, we focused on N-cadherin, which is involved in cell-cell adhesion, and proved whether STAT3/Pim-1/eIF4B/ N-cadherin signaling pathway in cardiomyocytes could work for cardioprotective effects.
The proposal from the results of this study may support the possibility of cardioprotective effect by cell-cell adhesion control through STAT3/Pim-1 signaling pathway.

Research Products

• [Journal Article] 2-aminoethoxydiphenyl borate provides an anti-oxidative effect and mediates cardioprotection during ischemia reperfusion in mice. (2017)
  • Author(s): Morihara H, Obana M, Tanaka S, Kawakatsu I, Tsuchiyama D, Mori S, Suizu H, Ishida A, Kimura R, Tsuchimochi I, Maeda M, Yoshimitsu T, Fujio Y, Nakayama H.
  • Journal Title: PLoS One. Volume: 12 Issue: 12 Pages: e0189948-e0189948
  • DOI: 10.1371/journal.pone.0189948
  • Peer Reviewed / Open Access
• [Journal Article] RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction. (2017)
  • Author(s): Enomoto D, Matsumoto K, Yamashita T, Kobayashi A, Maeda M, Nakayama H, Obana M, Fujio Y.
  • Journal Title: PLoS One. Volume: 12 Issue: 8 Pages: e0183584-e0183584
  • DOI: 10.1371/journal.pone.0183584
  • Peer Reviewed / Open Access
• [Journal Article] Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis. (2017)
  • Author(s): Miyawaki A, Obana M, Mitsuhara Y, Orimoto A, Nakayasu Y, Yamashita T, Fukada SI, Maeda M, Nakayama H, Fujio Y.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 1407-1407
  • DOI: 10.1038/s41598-017-01426-8
  • Peer Reviewed / Open Access
• [Journal Article] Phospholamban inhibition by a single dose administration of locked nucleic acid antisense oligonucleotide improves cardiac contractility in pressure overload-induced systolic dysfunction in mice. (2017)
  • Author(s): Morihara, H., Yamamoto, T., Oiwa, H., Tonegawa, K., Tsuchiyama, D., Kawakatsu, I., Obana, M., Maeda, M., Mohri, T., Obika, S., Fujio, Y., Nakayama, H.
  • Journal Title: J. Cardiovasc. Pharmacol. Ther. Volume: 印刷中 Issue: 3 Pages: 273-282
  • DOI: 10.1177/1074248416676392
  • Peer Reviewed / Open Access
• [Journal Article] Caveolae-specific activation loop between CaMKII and L-type Ca2+ channel aggravates cardiac hypertrophy in α1 adrenergic stimulation. (2017)
  • Author(s): Tonegawa, K., Otsuka, W., Kumagai, S., Matsunami, S., Hayamizu, N., Tanaka, S., Moriwaki, K., Obana, M., Maeda, M., Asahi, M., Kiyonari, H., Fujio, Y., Nakayama, H.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol. Volume: ３１２ Issue: 3 Pages: H501-H514
  • DOI: 10.1152/ajpheart.00601.2016
  • Peer Reviewed / Open Access
• [Journal Article] Four cases of investigational therapy with interleukin-11 against acute myocardial infarction. (2016)
  • Author(s): Nakagawa, M., Owada Y., Izumi, Y., Nonin, S., Sugioka, K., Nakatani, D., Iwata, S., Mizutani, K., Nishimura, S., It, A., Fujita, S., Daimon, T., Sawa, Y., Asakura, M., Maeda, M., Fujio, Y., Yoshiyama, M.
  • Journal Title: Heart and Vessels Volume: 31 Issue: 9 Pages: 1574-1578
  • DOI: 10.1007/s00380-015-0788-4
  • Peer Reviewed
• [Journal Article] Moesin is activated in cardiomyocytes in experimental autoimmune myocarditis and mediates cytoskeletal reorganization with protrusion formation (2016)
  • Author(s): Akimitsu Miyawaki, Yusuke Mitsuhara, Aya Orimoto, Yusuke Nakayasu, Shin-ichi Tsunoda, Masanori Obana, Makiko Maeda, Hiroyuki Nakayama, Yasuo Yoshioka, Yasuo Tsutsumi, Yasushi Fujio
  • Journal Title: The American Journal of Physiology-Heart and Circulatory Physiology Volume: 311 Issue: 2 Pages: 476-486
  • DOI: 10.1152/ajpheart.00180.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Four cases of investigational therapy with interleukin-11 against acute myocardial infarction. (2016)
  • Author(s): Nakagawa, M., Owada Y., Izumi, Y., Nonin, S., Sugioka, K., Iwata, S., Mizutani, K., Nishimura, S., It, A., Fujita, S., Daimon, T., Sawa, Y., Asakura, M., Maeda, M., Fujio, Y., Yoshiyama, M.
  • Journal Title: Heart and Vessels Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-27 induces the endothelial differentiation in Sca-1+ cardiac resident stem cells. (2015)
  • Author(s): Tanaka, T., Obana, M., Mohri, T., Maeda, M., Fujio, Y.
  • Journal Title: Cytokine Volume: 75 Issue: 2 Pages: 365-372
  • DOI: 10.1016/j.cyto.2015.06.009
  • Peer Reviewed / Open Access
• [Journal Article] Vascular functional and morphological alteration in smokers during varenicline therapy. (2015)
  • Author(s): Kobayashi, M., Takemoto, Y., Norioka, N., Iguchi, Y., Shimada, K., Maeda, M., Morimura, M., Fujio, Y., Azuma, ., Yoshiyama, M., Hirohashi, K., Shuto, T.
  • Journal Title: Osaka City Med. J. Volume: 61 Pages: 19-30
  • NAID: 120006493315
  • Peer Reviewed
• [Journal Article] Cardiac specific ablation of STAT3 gene in subacute phase of myocardial infarction exacerbated cardiac remodeling. (2015)
  • Author(s): Enomoto, D., Obana, M., Miyawaki, A., Maeda, M., Nakayama, H., Fujio, Y.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol. Volume: 3０９ Issue: 3 Pages: H471-H480
  • DOI: 10.1152/ajpheart.00730.2014
  • Peer Reviewed / Open Access
• [Presentation] Safety and feasibility report of investigational therapy with interleukin-11 against acute myocardial infarction (2017)
  • Author(s): Maeda, M., Nakagawa, M., Owada, Y., Izumi, Y., Nonin, S., Sugioka, K., Nakatani, D., Iwata,S., Mizutani, K., Nishimura, S., Ito, A., Fujita, S., Daimon, T., Sawa, Y., Asakura, M., Fujio, Y., Yoshiyama, M.
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Myofibroblast-specific deletion of Runx2 improves systolic function and survival in late phase of cardiac remodeling after myocardial infarction (2017)
  • Author(s): Tanaka, S., Enomoto, D., Yanase, E., Kumagi, S., Obana, M., Maeda, M., Fujio, Y., Nakayama, H.
  • Organizer: AHA Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] 心筋炎回復過程における心筋細胞の内因性増殖機構の解析 (2017)
  • Author(s): 折本彩、中安佑介、松井理紗、宮脇昭光、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 第132回 日本薬理学会近畿部会
• [Presentation] 腎線維化病態における転写因子OASISの役割 (2017)
  • Author(s): 守沖瞳、尾花理徳、山本彩葉、金本聡自、前田真貴子、今泉和則、中山博之、藤尾慈
  • Organizer: 第132回 日本薬理学会近畿部会
• [Presentation] 急性心筋梗塞に対するヒトIL-11製剤を用いた心筋保護治療（Interleukin-11 therapy for cardioprotection against acute myocardial infarction) (2017)
  • Author(s): 藤尾慈、前田真貴子、大門貴志、中谷大作、杉岡憲一、岩田真一、澤芳樹、朝倉正紀、泉康雄、葭山稔
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
• [Presentation] eIF4Bは、Pim-1キナーゼの下流における心筋細胞保護因子である (2017)
  • Author(s): 横山由加里 松本浩太朗 木下真希 尾花理徳 前田真貴子 中山博之 藤尾慈
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
• [Presentation] RORγtのヘテロ欠損は心筋梗塞後の心筋リモデリングを悪化させる（RORγt heterozygous deficiency aggravates cardiac remodeling after myocardial infarction） (2017)
  • Author(s): Enomoto D, Obana M, Matsumoto K, Maeda M, Nakayama H, Fujio Y.
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
• [Presentation] Moesinは実験的自己免疫性心筋炎モデルにおいて活性化し、仮足形成を伴う組織修復に関与する(Moesin is activated in cardiomyocytes in experimental autoimmune myocarditis and mediates tissue restoration with protrusion formation) (2017)
  • Author(s): Yusuke Mitsuhara, Akimitsu Miyawaki, Aya Orimoto, Yusuke Nakayasu, Shin-ichi Tsunoda, Masanori Obana, Makiko Maeda, Hiroyuki Nakayama, Yasuo Yoshioka, Yasuo Tsutsumi, Yasushi Fujio
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
• [Presentation] Pim-1を介したSTAT3による新規細胞保護機構の解明 (2016)
  • Author(s): 大谷勇太、横山由加里、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 日本薬学会136回
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] 心筋炎病態下におけるSTAT3を介した成体心筋細胞増殖 (2016)
  • Author(s): 宮脇昭光 高家圭紀 密原佑介 山下朋美 尾花理徳 前田真貴子 中山博之 藤尾慈
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-09
• [Presentation] Adult mammalian hearts restore intrinsic regenerative capacity through signal transducer and activator of transcription 3 in the resolution phase of myocarditis. (2016)
  • Author(s): Akimitsu Miyawaki, Masanori Obana, Yusuke Mitsuhara, Aya Orimoto, Yusuke Nakayasu, Tomomi Yamashita, So-ichiro Fukada, Makiko Maeda, Yasushi Sakata, Hiroyuki Nakayama, Yasushi Fujio
  • Organizer: American Heart Association Scientific Session 2016
  • Place of Presentation: New Orleans.USA
• [Presentation] Heterozygous ablation of RORγt gene deteriorates adverse cardiac remodeling after myocardial infarction (2016)
  • Author(s): Daichi Enomoto, Masanori Obana, Kotaro Matsumoto, Yasushi Sakata, Makiko Maeda, Hiroyuki Nakayama, Yasushi Fujio
  • Organizer: American Heart Association Scientific Session 2016
  • Place of Presentation: New Orleans.USA
• [Presentation] Cardiac STAT3 activation in subacute phase of myocardial infarction was required for the suppression of adverse cardiac remodeling (2015)
  • Author(s): Enomoto, D., Obana, M., Miyawaki, A., Maeda, m., Nakayama,H., Fujio, Y.
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Orlando
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Gp130サイトカインと心血管病 (2015)
  • Author(s): 藤尾 慈、前田真貴子、朝倉正紀、中谷大作、泉 康雄、葭山 稔
  • Organizer: 第1回、国際心血管薬物療法学会日本部会
  • Place of Presentation: 京都
  • Year and Date: 2015-06-20
  • Invited