A Study for Epigenetic Regulation to Maintain Cardiac Homeostasis

• Project/Area Number: 21689022
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: ASANO Yoshihiro 大阪大学, 大学院・医学系研究科, 助教 (60527670)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2011: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2010: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 分子心臓病態学 / エピゲノム / ヘテロクロマチン / クロマチン免疫沈降法 / 胎児性遺伝子 / ヒストン修飾 / ピストン修飾

Research Abstract

Sustained gene activation, such as" cardiac fetal gene reactivation", has an important role in the mechanism underlying exacerbations of chronic heart failure. However, the maintenance mechanism of its expressional activation has not yet been fully elucidated. We first found evidence for heterochromatin disruption in the nucleus of failing cardiomyocytes and paradoxical depression of cis-acting transcription factors, despite elevated levels of target cardiac fetal genes, suggesting that epigenetic gene regulation might be involved in this phenomenon. In addition, we newly developed in vivo chromatin immunoprecipitation assay, which has hardly been applied in the field of cardiac tissue. The proven alteration in transcriptional sensitivity by epigenetic gene modification was found to play a significant role in the" nuclear memory" mediating heart failure, raising the hope for the novel pathological understanding for chronic diseases.

Research Products

• [Journal Article] Development of anti-HB-EGF immunoliposomes for the treatment of breast cancer (2011)
  • Author(s): Nishikawa K, Asai T, Shigematsu H, Shimizu K, Kato H, Asano Y, Takashima S, Mekada E, Oku N, Minamino T
  • Journal Title: J Control Release Volume: (in press)
  • Peer Reviewed
• [Journal Article] A case of non-cardiogenic acute pulmonary edema in a patient with POEMS syndrome-associated pulmonary arterial hypertension (2011)
  • Author(s): Hara M, Mizote I, Nakaoka Y, Tanaka H, Asano Y, Sakata Y, Komuro I
  • Journal Title: Ann Hematol Volume: 90(4) Pages: 489-90
  • Peer Reviewed
• [Journal Article] The impact of cardiac resynchronization therapy in an end-stage heart failure patient with a left ventricular assist device as a bridge to recovery. A case report (2011)
  • Author(s): Muratsu J, Hara M, Mizote I, Asano Y, Sakata Y, Saito S, Matsumiya G, Sawa Y, Komuro I
  • Journal Title: Int Heart J Volume: 52(4) Pages: 246-7
  • Peer Reviewed
• [Journal Article] Clinical impact of off-label cardiac resynchronization therapy in end-stage heart failure patients on continuous intravenous inotrope (2011)
  • Author(s): Hara M, Mizuno H, Mizote I, Nakatani D, Asano Y, Sakata Y, Nanto S, Komuro I
  • Journal Title: Clin Cardiol Volume: 34(11) Pages: 714-20
  • Peer Reviewed
• [Journal Article] The Impact of Cardiac Resynchronization Therapy in an End-Stage Heart Failure Patient With a Left Ventricular Assist Device as a Bridge to Recovery A Case Report (2011)
  • Author(s): Muratsu J, Hara M, Mizote I, Asano Y, Sakata Y, Saito S, Matsumiya G, Sawa Y, Komuro I
  • Journal Title: International Heart Journal Volume: 52 Issue: 4 Pages: 246-247
  • DOI: 10.1536/ihj.52.246
  • NAID: 130000971171
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed
• [Journal Article] AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation (2010)
  • Author(s): Nakano A, Kato H, Watanabe T, Min KD, Yamazaki S, Asano Y, Seguchi O, Higo S, Shintani Y, Asanuma H, Asakura M, Minamino T, Kaibuchi K, Mochizuki N, Kitakaze M, Takashima S
  • Journal Title: Nature Cell Biology Volume: 12(6) Pages: 583-90
  • Peer Reviewed
• [Journal Article] Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1(HP1) (2010)
  • Author(s): Higo S, Asano Y, Kato H, Yamazaki S, Nakano A, Tsukamoto O, Seguchi O, Asai M, Asakura M, Asanuma H, Sanada S, Minamino T, Komuro I, Kitakaze M, Takashima S
  • Journal Title: J Biol Chem Volume: 285(41) Pages: 31337-47
  • Peer Reviewed
• [Journal Article] X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/ CRE-like element in cardiomyocytes (2010)
  • Author(s): Sawada T, Minamino T, Fu HY, Asai M, Okuda K, Isomura T, Yamazaki S, Asano Y, Okada K, Tsukamoto O, Sanada S, Asanuma H, Asakura M, Takashima S, Kitakaze M, Komuro I
  • Journal Title: J Mol Cell Cardiol Volume: 48(6) Pages: 1280-9
  • Peer Reviewed
• [Journal Article] Ablation of C/ EBP Homologous Protein Attenuates Endoplasmic Reticulum-Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload (2010)
  • Author(s): Fu HY, Okada KI, Liao Y, Tsukamoto O, Isomura T, Asai M, Sawada T, Okuda K, Asano Y, Sanada S, Asanuma H, Asakura M, Takashima S, Komuro I, Kitakaze M, Minamino T
  • Journal Title: Circulation Volume: 122(4) Pages: 361-9
  • Peer Reviewed
• [Journal Article] Sildenafil and steroid therapy effectively improved POEMS syndromeassociated pulmonary arterial hypertension (2010)
  • Author(s): Shimomura Y, Hara M, Mizote I, Nakaoka Y, Tanaka H, Asano Y, Sakata Y, Komuro I
  • Journal Title: Int J Hematol Volume: 92(5) Pages: 774-6
  • Peer Reviewed
• [Journal Article] Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1). (2010)
  • Author(s): Higo S, et al.
  • Journal Title: J Biol Chem. Volume: 285 Pages: 31337-47
  • Peer Reviewed
• [Journal Article] AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. (2010)
  • Author(s): Nakano A, et al.
  • Journal Title: Nature Cell Biology. Volume: 12 Pages: 583-590
  • Peer Reviewed
• [Journal Article] Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. (2010)
  • Author(s): Fu HY, et al.
  • Journal Title: Circulation. Volume: 122 Pages: 361-369
  • Peer Reviewed
• [Journal Article] X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocyte (2010)
  • Author(s): Sawada T, et al.
  • Journal Title: J Mol Cell Cardiol. (in press)
  • Peer Reviewed
• [Journal Article] Natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure (2009)
  • Author(s): Tsukamoto O, Fujita M, Kato M, Yamazaki S, Asano Y, Ogai A, Okazaki H, Asai M, Nagamachi Y, Maeda N, Shintani Y, Minamino T, Asakura M, Kishimoto I, Funahashi T, Tomoike H, Kitakaze M
  • Journal Title: J Am Coll Cardiol Volume: 53(22) Pages: 2070-7
  • Peer Reviewed
• [Journal Article] PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts (2009)
  • Author(s): Asai M, Tsukamoto O, Minamino T, Asanuma H, Fujita M, Asano Y, Takahama H, Sasaki H, Higo S, Asakura M, Takashima S, Hori M, Kitakaze M
  • Journal Title: J Mol Cell Cardiol Volume: 46(4) Pages: 452-62
  • Peer Reviewed
• [Journal Article] Natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure. (2009)
  • Author(s): Tsukamoto O, et al.
  • Journal Title: J Am Coll Cardiol. 53 Pages: 2070-2077
  • Peer Reviewed
• [Journal Article] PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts. (2009)
  • Author(s): Asai M, et al.
  • Journal Title: J Mol Cell Cardiol. 46 Pages: 452-462
  • Peer Reviewed
• [Presentation] Evidence for dynamic changes of chromatin state at the stress-induced gene locus in cardiomyocytes (2011)
  • Author(s): Shuichiro Higo, Yoshihiro Asano, Seiji Takashima, Issei Komuro
  • Organizer: Molecular Cardiovascular Conference
  • Place of Presentation: 北海道
  • Year and Date: 2011-09-03
• [Presentation] 心不全におけるクロマチンリモデリング制御と細胞機能維持機構の解明、成人病の病因・病態の解明に関する研究助成 (2011)
  • Author(s): 朝野仁裕
  • Organizer: 第17回研究発表会
  • Place of Presentation: 大阪
  • Year and Date: 2011-07-02
• [Presentation] 心不全におけるクロマチンリモデリング制御と細胞機能維持機構の解明 (2011)
  • Author(s): 朝野仁裕
  • Organizer: 成人病の病因・病態の解明に関する研究助成第17回研究発表会
  • Place of Presentation: 大阪
  • Year and Date: 2011-07-02
• [Presentation] 心不全の新しい病態解析法新しい心筋viability評価法の開発による治療抵抗性心不全へのアプローチ (2011)
  • Author(s): 朝野仁裕
  • Organizer: 大阪ハートクラブ学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2011-05-18
• [Presentation] 心不全の新しい病態解析法新しい心筋viability評価法の開発による治療抵抗性心不全へのアプローチ (2011)
  • Author(s): 朝野仁裕
  • Organizer: 大阪ハートクラブ
  • Place of Presentation: 大阪
  • Year and Date: 2011-05-18
• [Presentation] Heterochromatin Protein 1 Acts as an Intra-nuclear Redox Sensor (2010)
  • Author(s): Higo S, et al.
  • Organizer: American Heart Association Scientific Sessions 2010
  • Place of Presentation: アメリカ、シカゴ
  • Year and Date: 2010-11-16
• [Book] 心不全の原因・病態に迫る検査「遺伝子診断はどのような症例に行うべきか?」変貌する心不全診療 (2012)
  • Author(s): 朝野仁裕
  • Publisher: 南光堂
• [Book] 心不全の原因診断の進歩、心不全 (2012)
  • Author(s): 朝野仁裕、小室一成
  • Publisher: 診断と治療社
• [Book] 拡張型心筋症に関する新しい解析方法、CARDIAC PRACTICE (2011)
  • Author(s): 朝野仁裕
  • Publisher: メディカルレビュー社
• [Book] 最新・心不全Update-研究と臨床の最前線、心不全の先端的研究トピックス、心不全のジェネティクスとエピジェネティクス、医学のあゆみ (2010)
  • Author(s): 朝野仁裕、小室一成
  • Publisher: 医歯薬出版
• [Book] 心不全におけるクロマチンリモデリングの役割、Annual Review循環器 (2010)
  • Author(s): 朝野仁裕
  • Publisher: 中外医学社
• [Book] 医学の歩み 心不全-研究と臨床の最前線 1月第5曜特集号 (2010)
  • Author(s): 朝野仁裕、小室一成
  • Total Pages: 7
  • Publisher: 医歯薬出版社
• [Book] Annual Review 2010循環器 (2010)
  • Author(s): 朝野仁裕
  • Total Pages: 7
  • Publisher: 中外医学社
• [Book] Altered epigenetic memory with chromatin disruption in the end-stage failing heart.分子心血管病 (2009)
  • Author(s): 朝野仁裕
  • Publisher: 先端医学社