心不全発症における心筋p300/GATA4経路活性化メカニズムの解明

2011 Fiscal Year Annual Research Report

• Project/Area Number: 21590944
• Research Institution: University of Shizuoka
• Principal Investigator: 森本 達也 静岡県立大学, 薬学部, 教授 (50390779)
• Keywords: 心筋細胞肥大 / プロテオミクス / 転写因子 / GATA4 / p300

Research Abstract

我々は内因性ヒストンアセチル化酵素(HAT)活性を有するp300とGATA転写因子群の協力(p300/GATA経路)が心不全発症における遺伝子発現調節に極めて重要であることを示した。次に、p300/GATA経路の活性制御機構解明の為に、その結合蛋白を精製し、質量分析により網羅的に解析し73個同定した。本研究では、新規結合蛋白中の1つである、Nucleosome Remodelingand Deacetylase(NuRD)複合体構成因子RbAp48およびRbAp46に着目し、p300/GATA経路制御機構の詳細な解明を行った。
GST pull-downアッセイにより、RbAp48およびRbAp46はそれぞれGATA4だけでなく、p300とも直接結合した。HEK293細胞を用いて検討したところ、p300過剰発現によるGATA4のアセチル化およびGATA4とp300の結合をRbAp48、RbAp46は抑制した。次に、培養心筋細胞に、RbAp48あるいはRbAp46を過剰発現させると、肥大刺激であるフェニレフリンによるGATA4のアセチル化やDNA結合能、さらには心筋細胞肥大を抑制した。反対にshRNAでRbAp48、RbAp46をノックダウンすると、心筋細胞肥大を誘導することを見出した。また、蛍光免疫染色によりフェニレフリン刺激にて肥大を誘導すると、RbAp48、RbAp46が核外へ移行することを認められた。
さらなる詳細なメカニズムを解明することにより、p300/GATA4経路を制御する新規心不全治療薬のターゲットとなる可能性が示唆された。

Research Products

• [Journal Article] α1-Antitrypsin-low-density-lipoprotein Serves as a Marker of Smoking-specific Oxidative Stress (2012)
  • Author(s): Wada H, Ura S, Satoh-Asahara N, Kitaoka S, Mashiba S, Akao M, Abe M, Ono x, Morimoto T, Fujita M, Shimatsu A, Takahashi Y, Hasegawa K
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 19(1) Pages: 47-58
  • DOI: 10.5551/jat.9035
  • Peer Reviewed
• [Journal Article] Cyclin-dependent kinase 9 forms a complex with GATA4 and is involved in the differentiation of mouse ES cells into cardiomyocytes (2011)
  • Author(s): Kaichi S, Takaya T, Morimoto T, Sunagawa Y, Kawamura T, Ono K, Shimatsu A, Baba S, Heike T, Nakahata T, Hasegawa K
  • Journal Title: Journal of Cellular Physiology Volume: 226 Pages: 248-254
  • DOI: 10.1002/jcp.22336
  • Peer Reviewed
• [Journal Article] Distinct characteristics of circulating vascular endothelial growth factor-A and C levels in human subjects (2011)
  • Author(s): Wada H, Ura S, Kitaoka S, Satoh-Asahara N, Horie H, Ono K, Takaya T, Takanabe-Mori R, Akao M, Abe M, Morimoto T, Murayama T, Yokode M, Fujita M, Shimatsu A, Hasegawa K
  • Journal Title: PLoS ONE Volume: 6(12) Pages: e29351
  • DOI: 10.1371/journal.pone.0029351
  • Peer Reviewed
• [Journal Article] A Natural p300-Specific Histone Acetyltransferase Inhibitor, Curcumin, in Addition to Angiotensin-Converting Enzyme Inhibitor, Exerts Beneficial Effects on Left Ventricular Systolic Function After Myocardial Infarction in Rats (2011)
  • Author(s): Sunagawa Y, Morimoto T, Wada H, Takaya T, Katanasaka Y, Kawamura T, Yanagi S, Marui A, Sakata R, Shimatsu A, Kimura T, Kakeya H, Fujita M, Hasegawa K
  • Journal Title: Circulation Journal Volume: 75 Pages: 2151-2159
  • DOI: 10.1253/circj.CJ-10-1072
  • Peer Reviewed
• [Journal Article] Innovative preparation of curcumin for improved oral bioavailability (2011)
  • Author(s): Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, Wada H, atanasaka Y, Kakeya H, Fujita M, Hasegawa K, Morimoto T
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 34(5) Pages: 660-665
  • DOI: 10.1248/bpb.34.660
  • Peer Reviewed
• [Presentation] Human SNF5/INI1, a Component of the Human SWI/SNF Chromatin Remodeling Complex, Inhibits Hypertrophic Responses by Suppressing p300/GATA4-dependent Pathways in Cardiomyocytes (2012)
  • Author(s): Yoichi Sunagawa, Yukihiro Ishibashi, Natsumi Banno, Yasufumi Katanasaka, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-17
• [Presentation] Retinoblastoma Protein (Rb)-associated Protein 48 and 46, Novel p300/GATA4-binding Partners, Inhibits Hypertrophic Responses in Cardiomyocytes (2012)
  • Author(s): Yoichi Sunagawa, Yuichi Watanabe, Hidetoshi Suzuki, Yasufumi Katanasaka, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-17
• [Presentation] Transducin Beta-like Protein 1 Suppresses Hypertrophic Responses Through Repression of p300/GATA4 Pathway in Cardiomyocytes (2012)
  • Author(s): Masatoshi Namiki, Yasufumi Katanasaka, Yoichi Sunagawa, Hidetoshi Suzuki, Sho Hirota, Yukiko Nakagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-16
• [Presentation] Transducin beta-like protein 1 inhibits hypertrophic responses by recruiting HDAC3 to p300/GATA4 pathways (2011)
  • Author(s): Masatoshi Namiki, Yasufumi Katanasaka, Yoichi Sunagawa, Hidetoshi Suzuki, Sho Hirota, Taishi Terada, Yukiko Nakagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: The 7th Chica-Japan Cardiovascular Forum
  • Place of Presentation: Beijing, China
  • Year and Date: 20111014-15
• [Presentation] Receptor for activated protein kinase C1 is a novel component of p300/GATA4 complex and suppresses hypertrophic responses in cardiomyocytes (2011)
  • Author(s): Hidetoshi Suzuki, Yoichi Sunagawa, Yasufumi Katanasaka, Nobuko Okamura, Taishi Terada, Masatoshi Namiki, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: The 7th Chica-Japan Cardiovascular Forum
  • Place of Presentation: Beijing, China
  • Year and Date: 20111014-15
• [Presentation] Protein arginine metyltransferase 5 and methylosome protein 50 are novel component of p300/GATA4 complex involved in hypertrophic responses in cardiac myocytes (2011)
  • Author(s): Yasufumi Katanasaka, Yukiko Nakagawa, Yoichi Sunagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: American Heart Association BCVS2011
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20110718-21
• [Presentation] Receptor for Activated Protein Kinase C1 is a novel component of p300/GATA4 complex and required for hypertrophic responses in cardiac myocytes (2011)
  • Author(s): Hidetoshi Suzuki, Yoichi Sunagawa, Yasufumi Katanasaka, Nobuko Okamura, Taishi Terada, Masatoshi Namiki, Yukiko Nakagawa, Akihisa Sugimoto, Hiromichi Wada, Akira Shimatsu, Takeshi Kimura, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 第28回国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-12-02
• [Presentation] Transducin beta-like protein 1 suppresses p300/GATA4-induced hypertrophic responses in cardiomyocytes (2011)
  • Author(s): Masatoshi Namiki, Yasufumi Katanasaka, Yoichi Sunagawa, Hidetoshi Suzuki, Sho Hirota, Taishi Terada, Yukiko Nakagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 第28回国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-12-02
• [Presentation] SNF5/INI1 Inhibits Hypertrophic Responses by Suppressing p300/GATA4-dependent Pathways in Cardiomyocytes (2011)
  • Author(s): Yoichi Sunagawa, Sugimoto Akihisa, Yukihiro Ishibashi, Yasufumi Katanasaka, Hiromichi Wada, Akira Shimatsu, Takeshi Kimura, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-15
• [Presentation] Retinoblastoma Protein (Rb)-associated Protein 48 and 46 Form a Functional Complex With p300/GATA4 and Suppress Hypertrophic Responses in Cardiomyocytes (2011)
  • Author(s): Yoichi Sunagawa, Yasufumi Katanasaka, Taishi Terada, Yuichi Watanabe, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-15
• [Presentation] Protein Arginine Methyltransferase 5 and Methylosome Protein 50 Suppressies Hypertrophic Responses in Cardiomyocytes by Inhibition of p300/GATA4 Pathway (2011)
  • Author(s): Yasufumi Katanasaka, Yukiko Nakagawa, Yoichi Sunagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-13
• [Presentation] A P300/GATA4 transcriptional pathway that induces the development of heart failure (2011)
  • Author(s): Tatsuya Morimoto, Koji Hasegawa
  • Organizer: The 7th Chica-Japan Cardiovascular Forum
  • Place of Presentation: Beijing, China
  • Year and Date: 2011-10-15
• [Presentation] Protein arginine ethyltransferase 5 suppresses hypertrophic gene transcription in rat cardiomyocytes through the inhibition of P300/GATA4 pathway (2011)
  • Author(s): Yasufumi Katanasaka, Yukiko Nakagawa, Yoichi Sunagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: The 7th Chica-Japan Cardiovascular Forum
  • Place of Presentation: Beijing, China
  • Year and Date: 2011-10-15
• [Presentation] Retinoblastoma protein (Rb)-associated protein 48 and 46 are novel p300/GATA4-binding partners involved in hypertrophic responses in cardiomyocytes (2011)
  • Author(s): Yoichi Sunagawa, Yasufumi Katanasaka, Taishi Terada, Yuichi Watanabe, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 第15回日本心不全学会学術集会会
  • Place of Presentation: 鹿児島
  • Year and Date: 2011-10-14
• [Presentation] Retinoblastoma protein (Rb)-associated protein 48 and 46 are novel p300/GATA4-binding partners involved in hypertrophic responses in cardiomyocytes (2011)
  • Author(s): Yoichi Sunagawa, Yasufumi Katanasaka, Taishi Terada, Yuichi Watanabe, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: American Heart Association BCVS2011
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2011-07-20
• [Presentation] Retinoblastoma protein (Rb)-associated protein 48 and 46 are novel components of p300/GATA4 complex required for hypertrophic responses in cardiomyocytes (2011)
  • Author(s): Yoichi Sunagawa, Yasufumi Katanasaka, Taishi Terada, Yuichi Watanabe, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: The 14 th Annual International Tronto Heart Summit
  • Place of Presentation: Tronto, Canada
  • Year and Date: 2011-06-09
• [Presentation] Protein arginine metyltransferase 5 and methylosome protein 50 are novel component of P300/GATA4 complex involved in hypertrophic responses in cardiac myocytes (2011)
  • Author(s): Yasufumi Katanasaka, Yukiko Nakagawa, Yoichi Sunagawa, Masatoshi Fujita, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: The 14 th Annual International Tronto Heart Summit
  • Place of Presentation: Tronto, Canada
  • Year and Date: 2011-06-09
• [Presentation] 新しい心不全分子標的治療 (2011)
  • Author(s): 森本達也、長谷川浩二
  • Organizer: 第11回日本抗加齢医学会総会
  • Place of Presentation: 京都
  • Year and Date: 2011-05-27