The molecular and cellular mechanism of myocardial repair/regeneration

• Project/Area Number: 26293054
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Osaka University
• Principal Investigator: FUJIO Yasushi 大阪大学, 薬学研究科(研究院), 教授 (20359839)
• Co-Investigator(Kenkyū-buntansha): 毛利 友美 大阪大学, 薬学研究科(研究院), 研究員 (20572960) ; 中山 博之 大阪大学, 薬学研究科(研究院), 准教授 (40581062)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2014: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 心臓 / 組織修復・再生 / 心筋細胞増殖 / 細胞骨格 / 心筋炎 / STAT3 / 循環器・高血圧 / 心筋組織修復 / 炎症 / サイトカイン / Moesin / 心血管・血液 / 心筋 / 再生

Outline of Final Research Achievements

As mammalian cardiomyocytes substantially cease to proliferate immediately after birth, it has been believed that adult mammalian hearts show only limited regenerative capacities. However, clinically, most cases of acute myocarditis are self-limiting with myocardial recovery. Thus, we hypothesized that adult cardiomyocytes might restore regenerative activities during the healing process of myocarditis. In this study, using experimental autoimmune myocarditis (EAM) model, we addressed this hypothesis from two viewpoints; One is phenotypic modulation of cardiomyocytes and the other is cardiomyocyte proliferation. As for phenotypic modulation, proteomics analysis revealed that the expression of moesin, a cytoskeletal protein, was upregulated in cardiomyocytes, leading to the protrusion formation. As for cell proliferation, we detected cell cycle marker-positive cardiomyocytes at the beginning of the myocardial recovery, proposing the unexpected adult cardiomyocyte proliferation.

Research Products

• [Journal Article] A mouse model of Epstein-Barr virus LMP1 and LMP2A driven germinal center B-cell lymphoproliferative disease. (2017)
  • Author(s): 1Minamitani, T., Ma, Y., Zhou, H., Kida, H., Tsai, C.-Y., Obana, M., Okuzaki, D., Fujio, Y., Kumanogoh, A., Kikutani, H., Zhao, B., Kieff, E., Gewuz, B. E., Yasui, T.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 印刷中 Issue: 18 Pages: 4751-4756
  • DOI: 10.1073/pnas.1701836114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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, S., Maeda, M., Nakayama, H., Fujio, Y.
  • Journal Title: Sci. Rep. Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 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., 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] Myeloid cell-derived LRG attenuates adverse cardiac remodeling after myocardial infarction. (2016)
  • Author(s): Kumagai, S., Nakayama, H., Fujiomoto, M., Honda, H., Serada, S., Ishibashi-Ueda, H., Kasai, A., Obana, M., Sawa, Y., Fujio, Y., Naka, T.
  • Journal Title: Cardiovasc. Res. Volume: 109 Issue: 2 Pages: 272-282
  • DOI: 10.1093/cvr/cvv273
  • 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: 印刷中
  • 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
• [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] The Inhibition of N-Glycosylation of Glycoprotein 130 Molecule Abolishes STAT3 Activation by IL-6 Family Cytokines in Cultured Cardiac Myocytes. (2014)
  • Author(s): Matsuo R, Morihara H, Mohri T, Murasawa S, Takewaki K, Nakayama H, Maeda M, Fujio Y.
  • Journal Title: PLoS One Volume: 23 Issue: 10 Pages: e111097-e111097
  • DOI: 10.1371/journal.pone.0111097
  • Peer Reviewed / Open Access
• [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 (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: 長崎県長崎市
  • Year and Date: 2017-03-15
  • Invited
• [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: 長崎県長崎市
  • Year and Date: 2017-03-15
• [Presentation] RORgammat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 (2017)
  • Author(s): 榎本大智 尾花理徳 松本浩太朗 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: 長崎県長崎市
  • Year and Date: 2017-03-15
• [Presentation] 骨髄細胞特異的Runx2の欠損は心筋梗塞後の心筋リモデリングを悪化させる (2017)
  • Author(s): 芦塚萌 熊谷渉平 柳瀬絵美子 松本浩太朗 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: 長崎県長崎市
  • Year and Date: 2017-03-15
• [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 (2017)
  • Author(s): 密原佑介 宮脇昭光 折本彩 中安祐介 角田慎一 尾花理徳 前田真貴子 中山博之 吉岡靖雄 堤康央 藤尾慈
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎県長崎市
  • Year and Date: 2017-03-15
• [Presentation] Heterozygous ablation of RORγt gene deteriorates adverse cardiac remodeling after myocardial infarction. (2016)
  • Author(s): Enomoto, D., Obana, M., Matsumoto, K., Sakata, Y., Maeda, M., Nakayama, H., Fujio, Y.
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans. USA.
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Myeloid cell-specific Runx2 deficiency exacerbates adverse cardiac remodeling after myocardial infarction. (2016)
  • Author(s): Ashizuka, M., Kumagai, S., Yanase, E., Obana, M., Maeda, M., Sakata, Y., Nakayama, H., Fujio, Y.
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans. USA.
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Fibroblast-specific beta2 adrenergic receptor signaling regulates cardiac hypertrophy in mice. (2016)
  • Author(s): Tonegawa, K., Tanaka, S., Takahashi, M., Fuchigami, S., Obana, M., Maeda, M., Sakata, Y., Fujio, Y,. Nakayama, H.
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans. USA.
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [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): Miyawaki, A., Obana, M., Mitsuhara, Y., Orimoto, A., Nakayasu, Y., Yamashita, T., Fukada, S., Maeda, M., Sakata, Y., Nakayama, H., Fujio, Y.
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans. USA.
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [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 パシフィコ横浜
  • Year and Date: 2016-03-09
• [Presentation] Myeloid Cell Derived Leucine Rich α2 Glycoprotein Attenuates AdverseCardiac Remodeling After Myocardial Infarction. (2015)
  • Author(s): Shohei Kumagai, Hiroyuki Nakayama, Minoru Fujimoto, Hiromi Honda, Satoshi Serada, Atsushi Kasai, Masanori Obana, Yasushi Sakata, Yoshiki Sawa, Tetsuji Naka, Yasushi Fujio
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Ｏｒｌａｎｄｏ
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Blockade of NKG2D/NKG2D Ligands Interaction Attenuated Cardiac Remodeling after Myocardial Infarction (2015)
  • Author(s): Kotaro Matsumoto, Masanori Obana, Rina Hashidzume, Yukari Yokoyama,Nakayama, Shigeru Miyagawa, Tomomi Mohri, Makiko Maeda, Yasushi Sakata, Hiroyuki Nakayama, Yoshiki Sawa, Yasushi Fujio
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Orlando
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Cardiac STAT3 activation in subacute phase of myocardial infarction was required for the suppression of adverse cardiac remodeling (2015)
  • Author(s): Daichi Eonomoto, Masanori Obana, Akimitsu Miyawaki, Makiko Maeda, Hiroyuki Nakayama, Yasushi Fujio
  • 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 ハイアットリージェンシー京都
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] Interleukin 27 induces endothelial differentiation in murine cardiac stem cells (2015)
  • Author(s): 田中智大、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Elucidation of molecular mechanism of cardiomyocyte necrosis induced by reactive oxygen species. (2015)
  • Author(s): 土山大介、中山博之、森原啓文、石田瑛子、尾花理徳、前田真貴子、藤尾慈
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] IL-27 negatively regulates murine experimental autoimmune myocarditis (EAM). (2015)
  • Author(s): 古谷知佳、宮脇昭光、大谷勇太、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Adrenergic receptors β2 and β3 transduce differential signalsin cardiac fibroblasts. (2015)
  • Author(s): 五十嵐裕美、中山博之、松浪佐知、早水菜穂、舎川洸太、尾花理徳、前田真貴子、藤尾慈
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] The properties of cardiac Sca-1+ resident stem cells are altered in response to myocardial inflammation. (2015)
  • Author(s): 松原由実、宮脇昭光、榎原正貴、尾花理徳、前田真貴子、中山博之、藤尾慈
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Caveolae-specific phosphorylation of L-type calcium channel b2a subunit exaggerates cardiac hypertrophic responses after a1 adrenergic stimulation in mice (2014)
  • Author(s): Hiroyuki Nakayama, Shohei Kumagai, Sachi Matsunami, Nao Hayamizu, Kota Tonegawa, Wataru Otsuka, Yasushi Fujio
  • Organizer: International Society of Heart Research 日本部会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] Caveolae-specific phosphorylation of L-type calcium channel beta2a subunit excerbates cardiac hypertrophy (2014)
  • Author(s): Shohei Kumagai, Hiroyuki Nakayama, Nao Hayamizu, Wataru Otsuka, Yasushi Fujio
  • Organizer: American Heart Association, Scientific Sessions 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Caveolae-specific phosphorylation of L-type calcium channel b2a subunit exaggerates cardiac hypertrophic responses after a1 adrenergic stimulation in mice. (2014)
  • Author(s): Hiroyuki Nakayama, Shohei Kumagai, Sachi Matsunami, Nao Hayamizu, Kota Tonegawa, Wataru Otsuka , Yasushi Fujio
  • Organizer: American Heart Association, Basic Cardiovascular Sciences
  • Place of Presentation: Las Vegas, USA
  • Year and Date: 2014-07-13 – 2014-07-18