Roles of extracellular environment and various cells carrying different function for cardiac fibrosis

• Project/Area Number: 25253011
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Kyushu University
• Principal Investigator: KUROSE HITOSHI 九州大学, 薬学研究院, 教授 (10183039)
• Co-Investigator(Kenkyū-buntansha): 仲矢 道雄 九州大学, 薬学研究科(研究院), 准教授 (80464387) ; 長坂 明臣 九州大学, 薬学研究科(研究院), 助教 (10723877)
• Project Period (FY): 2013-10-21 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥44,330,000 (Direct Cost: ¥34,100,000、Indirect Cost: ¥10,230,000); Fiscal Year 2016: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000); Fiscal Year 2015: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000); Fiscal Year 2014: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000); Fiscal Year 2013: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
• Keywords: 筋線維芽細胞 / 心筋梗塞 / 死細胞 / 抗炎症作用 / 免疫細胞 / 線維芽細胞 / 貪食 / 炎症 / 線維化 / 薬理学 / シグナル伝達 / 循環器・高血圧 / 免疫学 / 細胞外微小環境

Outline of Final Research Achievements

Heart often develops heart failure after myocardial infarction, if proper revascularization is not provided. Inflammatory responses are believed to be a factor to progress to heart failure after myocardial infarction. As inflammation is induced by the cellular components released from dead cells, the quick and efficient removal of dead cells in myocardial infarction is important for preventing the development of heart failure. So far, phagocytes such as macrophages and dendritic cells infiltrating infarct area are supposed to be the players of removing dead cells. In this study, myofibroblasts remove dead cell as well as phagocytes do. The removal of dead cells by myofibroblasts requires MFG-E8 that bridges between apoptotic cells and phagocytes. Thus, myofibroblasts remove dead cells after myocardial infarction, and suppress the progression to heart failure.

Research Products

• [Int'l Joint Research] Dr. Nebigil CG./University of Strasbourg(France)
• [Journal Article] β-Adrenergic Receptor and Insulin Resistance in the Heart. (2017)
  • Author(s): Mangmool S, Denkaew T, Parichatikanond W, Kurose H.
  • Journal Title: Biomol Ther (Seoul). Volume: 25 Issue: 1 Pages: 44-56
  • DOI: 10.4062/biomolther.2016.128
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. (2017)
  • Author(s): Michio Nakaya,Kenji Watari,Mitsuru Tajima,Takeo Nakaya,Shoichi Matsuda,Hiroki Ohara,Hiroaki Nishihara,Hiroshi Yamaguchi,Akiko Hashimoto,Mitsuho Nishida,Akiomi Nagasaka,Yuma Horii,Hiroki Ono,Gentaro Iribe,Ryuji Inoue,Makoto Tsuda,Kazuhide Inoue,Akira Tanaka,Masahiko Kuroda,Shigekazu Nagata,Hitoshi Kurose
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 1 Pages: 383-401
  • DOI: 10.1172/jci83822
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Myofibroblasts and inflammatory cells as players of cardiac fibrosis. (2016)
  • Author(s): Kurose H, Mangmool S.
  • Journal Title: Arch Pharm Res. Volume: 39 Issue: 8 Pages: 1100-1113
  • DOI: 10.1007/s12272-016-0809-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction (2016)
  • Author(s): Hayato Fukuda, Saki Ito, Kenji Watari, Chihiro Mogi, Mitsuhiro Arisawa, Fumikazu Okajima, Hitoshi Kurose, Satoshi Shuto
  • Journal Title: ACS Med. Chem. Lett. Volume: 7 Issue: 5 Pages: 493-497
  • DOI: 10.1021/acsmedchemlett.6b00014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The purinergic P2Y6 receptor heterodimerizes with the angiotensin AT1 receptor to promote angiotensin II-induced hypertension (2016)
  • Author(s): A. Nishimura, C. Sunggip, H. Tozaki-Saitoh, T. Shimauchi, T. Numaga-Tomita, K. Hirano, T. Ide, J-M. Boeynaems, H. Kurose, M. Tsuda, B. Robaye, K. Inoue and M. Nishida
  • Journal Title: Science Signaling Volume: Jan 19;9(411) Issue: 411
  • DOI: 10.1126/scisignal.aac9187
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A new approach of indirect enzyme-linked immunosorbent assay for determination of D-glutamic acid through in situ conjugation (2016)
  • Author(s): Sakamoto, S., Nagamitsu, R., Matsuura, Y., Tsuneura, Y., Kurose, H., Tanaka, H.*, Morimoto, S.
  • Journal Title: Journal of Immunoassay and Immunochemistry Volume: 37 Issue: 3 Pages: 296-306
  • DOI: 10.1080/15321819.2015.1135161
  • Peer Reviewed
• [Journal Article] Discovery and cardioprotective effects of the first non-Peptide agonists of the g protein-coupled prokineticin receptor-1. (2015)
  • Author(s): Gasser A, Brogi S, Urayama K, Nishi T, Kurose H, Tafi A, Ribeiro N, Désaubry L, Nebigil CG.
  • Journal Title: PLoS One Volume: 10 Issue: 4 Pages: e0121027-e0121027
  • DOI: 10.1371/journal.pone.0121027
  • Peer Reviewed / Open Access
• [Journal Article] GRK6 phosphorylates IκBα at Ser32/Ser36 and enhances TNF-α-induced inflammation (2015)
  • Author(s): Yuki Ohba, Michio Nakaya*, Kenji Watari, Akiomi Nagasaka, & Hitoshi Kurose.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 461 Issue: 2 Pages: 307-313
  • DOI: 10.1016/j.bbrc.2015.04.027
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Imidazopyridine Compounds as Negative Allosteric Modulators of Proton- Sensing GPR4 in Extracellular Acidification-Induced Responses (2015)
  • Author(s): Ayaka Tobo, Masayuki Tobo, Takashi Nakakura, Masashi Ebara, Hideaki Tomura, Chihiro Mogi, Dong-Soon Im, Naoya Murata, Atsushi Kuwabara, Saki Ito, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto, Michio Nakaya, Hitoshi Kurose, Koichi Sato, Fumikazu Okajima
  • Journal Title: PLoS One. Volume: 10 Issue: 6 Pages: e0129334-e0129334
  • DOI: 10.1371/journal.pone.0129334
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of a new molecule that promotes clearance of apoptotic cells — G protein-coupled receptor kinase 6 is involved in engulfment of apoptotic cells (2015)
  • Author(s): 仲矢道雄、黒瀬等
  • Journal Title: Folia Pharmacologica Japonica Volume: 145 Issue: 1 Pages: 14-20
  • DOI: 10.1254/fpj.145.14
  • NAID: 130004827709
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Multiple functions of G protein-coupled receptor kinases (2014)
  • Author(s): Watari K, Nakaya M, Kurose H
  • Journal Title: Journal of Molecular Signaling Volume: 9 Pages: 1-1
  • DOI: 10.1186/1750-2187-9-1
  • Peer Reviewed / Open Access
• [Journal Article] Attenuated desensitization of -adrenergic receptor by water-soluble N-nitrosamines that induce S-nitrosylation without nitric oxide release. (2013)
  • Author(s): Makita N, Kabasawa Y, Otani Y, Firman F, Sato J, Hashimoto M, Nakaya M, Nishihara H, Nangaku M, Kurose H, Ohwada T and Iiri T.
  • Journal Title: Circ. Res. Volume: 112 Pages: 327-334
  • Peer Reviewed
• [Journal Article] Multiple signaling routes involved in the regulation of adenylyl cyclase and extracellular regulated kinase by dopamine D(2) and D(3) receptors. (2013)
  • Author(s): Jin M, Min C, Zheng M, Cho DI, Cheong SJ, Kurose H, Kim KM.
  • Journal Title: Pharmacol. Res. Volume: 67 Pages: 31-41
  • Peer Reviewed
• [Journal Article] A Novel Regulatory Function of Sweet Taste-Sensing Receptor in Adipogenic Differentiation of 3T3-L1 Cells. (2013)
  • Author(s): Masubuchi Y, Nakagawa Y, Ma J, Sasaki T, Kitamura T, Yamamoto Y, Kurose H, Kojima I, Shibata H.
  • Journal Title: PLoS ONE Volume: 8
  • Peer Reviewed
• [Journal Article] Increased ubiquitination and the crosstalk of G protein signaling in cardiac myocytes: involvement of Ric-8B in Gs suppression by Gq signal. (2013)
  • Author(s): Jenie RI, Nishimura M, Fujino M, Nakaya M, Mizuno N, Tago K, Kurose H, Itoh H.
  • Journal Title: Genes Cells Volume: 18 Pages: 1095-1106
  • Peer Reviewed
• [Presentation] 心肥大時に生じる死細胞はMFG-E8を介して貪食除去される (2017)
  • Author(s): 松田翔一、仲矢道雄、小宮詩織、長坂明臣、黒瀬等
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台市仙台国際センター、東北大学川内北キャンパス
  • Year and Date: 2017-03-24
• [Presentation] BLT1は心筋梗塞時における炎症を悪化させる (2017)
  • Author(s): 堀井雄真、仲矢道雄、西原弘朗、大原広貴、渡健治、長坂明臣、黒瀬等
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール、長崎新聞文化ホール アストピア
  • Year and Date: 2017-03-15
• [Presentation] The role of GRK2 in BMP signaling (2017)
  • Author(s): Yuki Ohba, Michio Nakaya, Akiomi Nagasaka, Hitoshi Kurose
  • Organizer: International Students' Science Camp of Kyushu University KAIST-Kyushu University Joint Seminar
  • Place of Presentation: Shikanoshima, Fukuoka
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] 心肥大時に生じる死細胞はMFG-E8を介して除去される (2016)
  • Author(s): 松田翔一、仲矢道雄、小宮詩織、長坂明臣、黒瀬等
  • Organizer: 第15回 次世代を担う若手ファーマ・バイオフォーラム2016
  • Place of Presentation: 大阪大学吹田地区薬学キャンパス
  • Year and Date: 2016-09-09
• [Presentation] 心筋梗塞時の死細胞を除去するメカニズム (2016)
  • Author(s): 仲矢道雄、渡健治、黒瀬等
  • Organizer: 第15回生命科学研究会
  • Place of Presentation: メルパルク東京
  • Year and Date: 2016-06-24
• [Presentation] 心筋梗塞時にGタンパク質共役型受容体によって仲介される応答 (2016)
  • Author(s): 黒瀬等
  • Organizer: 第８９回 日本薬理学会年会
  • Place of Presentation: 横浜パシフィコ（神奈川）
  • Year and Date: 2016-03-09
  • Invited
• [Presentation] 心筋梗塞におけるpH感知性GPCR（TDAG8）の役割解析 (2015)
  • Author(s): 西俊英、長坂明臣、小野達貴、仲矢道雄、黒瀬等
  • Organizer: 第14回 生命科学研究会
  • Place of Presentation: 三浦市民ホール（三浦市三崎、神奈川）
  • Year and Date: 2015-06-27
• [Presentation] 心筋梗塞時におけるプロトン感知性受容体（TDAG8)の役割解明 (2015)
  • Author(s): 西俊英、長坂明臣、仲矢道雄、岡島史和、黒瀬等
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場、名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] βアレスチンを介したバイアス型シグナリング (2015)
  • Author(s): 黒瀬等
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場、名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
  • Invited
• [Presentation] 心肥大時に生じるアポトーシス細胞はMFG-E8を介して除去される (2014)
  • Author(s): 松田翔一、仲矢道雄、小宮詩織、長坂明臣、黒瀬等
  • Organizer: 第67回日本薬理学会西南部会
  • Place of Presentation: 産業医科大学ラマツィーニホール、福岡
  • Year and Date: 2014-11-23
• [Presentation] The Physiological and pathological roles of cardiac fibroblasts (2014)
  • Author(s): 黒瀬等、仲矢道雄
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都国際会館、京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 心肥大におけるMFG-E8の役割解明 (2014)
  • Author(s): 松田翔一、仲矢道雄、小宮詩織、長坂明臣、黒瀬等
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2014
  • Place of Presentation: 大阪、近畿大学
  • Year and Date: 2014-08-30 – 2014-08-31
• [Presentation] 心筋梗塞時に生じる炎症応答における線維芽細胞の役割 (2014)
  • Author(s): 黒瀬等、仲矢道雄
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島大学 郡元キャンパス
  • Invited
• [Presentation] β-アレスチン2による心筋梗塞後の炎症応答抑制メカニズムの解明 (2013)
  • Author(s): 渡健治、仲矢道雄、黒瀬等
  • Organizer: 第66回 日本薬理学会西南部会
  • Place of Presentation: 福岡大学薬学部
• [Book] バイアス型シグナル (2016)
  • Author(s): 黒瀬等
  • Total Pages: 6
  • Publisher: 医歯薬出版株式会社
• [Book] βアドレナリン受容体 (2016)
  • Author(s): 黒瀬等
  • Total Pages: 7
  • Publisher: 医歯薬出版株式会社
• [Remarks] 研究室ホームページ
  • URL: http://chudoku.phar.kyushu-u.ac.jp/