Development of treatment of heart failure targetting at chronic organ damage and chromatin remodeling

• Project/Area Number: 24659380
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamagata University
• Principal Investigator: KUBOTA Isao 山形大学, 医学部, 教授 (30161673)
• Co-Investigator(Kenkyū-buntansha): SHISHIDO Tetsuro 山形大学, 医学部, 助教 (60400545)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 慢性心不全 / 胎児型遺伝子 / アセチル化 / クロマチン

Research Abstract

High Mobility Group Box 1 (HMGB1) is a nuclear DNA-binding protein that has multiple functions, however little is known about the effects of nuclear HMGB1 on fetal gene expressions under hypertrophic stimulation. We observed decreased nuclear HMGB1 expression in human failing hearts and pressure overloaded mice heart. Nuclear HMGB1 decreased in response to endothelin-1 (ET-1) or angiotensin II (ATII) stimulation in cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 or ATII induced fetal gene expression such as ANP and BNP and induction of cardiomyocyte hypertrophy. These results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure.

Research Products

• [Journal Article] Midkine exacerbates pressure overload-induced cardiac remodeling (2014)
  • Author(s): Netsu S, Shishido T, Kitahara T, Honda Y, Funayama A, Narumi T, Kadowaki S, Takahashi H, Miyamoto T, Arimoto T, Nishiyama S, Watanabe T, Woo CH, Takeishi Y, Kubota I.
  • Journal Title: Biochem Biophys Res Commun Volume: 443 Pages: 205-210
  • Peer Reviewed
• [Journal Article] Atrial endothelial impairment through Toll-like receptor 4 signaling causes atrial thrombogenesis (2014)
  • Author(s): Katoh S, Honda S, Watanabe T, Suzuki S, Ishino M, Kitahara T, Funayama A, Netsu S, Sasaki T, Shishido T, Miyamoto T, Sadahiro M, Kubota I.
  • Journal Title: Heart Vessels Volume: 29 Pages: 263-272
  • Peer Reviewed
• [Journal Article] Diacylglycerol kinaseαexacerbates cardiac injury after ischemia/reperfusion (2014)
  • Author(s): Sasaki T, Shishido T, Kadowaki S, Kitahara T, Suzuki S, Katoh S, Funayama A, Netsu S, Watanabe T, Goto K, Takeishi Y, Kubota I.
  • Journal Title: Heart Vessels Volume: 29 Pages: 110-118
  • Peer Reviewed
• [Journal Article] Midkine exacerbates pressure overload-induced cardiac remodeling. (2014)
  • Author(s): Netsu S, Shishido T, Kitahara T, Honda Y, Funayama A, Narumi T, Kadowaki S, Takahashi H, Miyamoto T, Arimoto T, Nishiyama S, Watanabe T, Woo CH, Takeishi Y, Kubota I.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Issue: 1 Pages: 205-210
  • DOI: 10.1016/j.bbrc.2013.11.083
  • Peer Reviewed / Open Access
• [Journal Article] Atrial endothelial impairment through Toll-like receptor 4 signaling causes atrial thrombogenesis. (2014)
  • Author(s): Katoh S, Honda S, Watanabe T, Suzuki S, Ishino M, Kitahara T, Funayama A, Netsu S, Sasaki T, Shishido T, Miyamoto T, Sadahiro M, Kubota I.
  • Journal Title: Heart Vessels. Volume: 29 Issue: 2 Pages: 263-272
  • DOI: 10.1007/s00380-013-0369-3
  • Peer Reviewed
• [Journal Article] Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure (2013)
  • Author(s): Funayama A, Shishido T, Netsu S, Narumi T, Kadowaki S, Takahashi H, Miyamoto T, Watanabe T, Woo CH, Abe J, Kuwahara K, Nakao K, Takeishi Y, Kubota I.
  • Journal Title: Cardiovasc Res Volume: 99 Pages: 657-664
  • Peer Reviewed
• [Journal Article] The impact of renal tubular damage, as assessed by urinaryβ2-microglobulin-creatinine ratio, on cardiac prognosis in patients with chronic heart failure (2013)
  • Author(s): Otaki Y, Watanabe T, Shishido T, Takahashi H, Funayama A, Narumi T, Kadowaki S, Hasegawa H, Honda S, Netsu S, Ishino M, Arimoto T, Miyashita T, Miyamoto T, Konta T, Kubota I.
  • Journal Title: Circ Heart Fail Volume: 6 Pages: 662-668
  • Peer Reviewed
• [Journal Article] Long Pentraxin PTX3 Exacerbates Pressure Overload-Induced Left Ventricular Dysfunction (2013)
  • Author(s): Suzuki S, Shishido T, Funayama A, Netsu S, Ishino M, Kitahara T, Sasaki T, Katoh S, Otaki Y, Watanabe T, Shibata Y, Mantovani A, Takeishi Y, Kubota I.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Senescence marker protein 30 has a cardio-protective role in doxorubicin-induced cardiac dysfunction (2013)
  • Author(s): Miyata M, Suzuki S, Misaka T, Shishido T, Saitoh S, Ishigami A, Kubota I, Takeishi Y
  • Journal Title: PLoS One Volume: 8 Issue: 12 Pages: e79093-e79093
  • DOI: 10.1371/journal.pone.0079093
  • Peer Reviewed
• [Journal Article] Senescence marker protein 30 inhibits angiotensin II-induced cardiac hypertrophy and diastolic dysfunction (2013)
  • Author(s): Misaka T, Suzuki S, Miyata M, Kobayashi A, Ishigami A, Shishido T, Saitoh S, Kubota I, Takeishi Y
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 439 Issue: 1 Pages: 142-147
  • DOI: 10.1016/j.bbrc.2013.08.002
  • Peer Reviewed
• [Journal Article] Deficiency of senescence marker protein 30 exacerbates angiotensin II-induced cardiac remodelling (2013)
  • Author(s): Misaka T, Suzuki S, Miyata M, Kobayashi A, Shishido T, Ishigami A, Saitoh S, Hirose M, Kubota I, Takeishi Y
  • Journal Title: Cardiovascular Research Volume: 9 Issue: 3 Pages: 461-470
  • DOI: 10.1093/cvr/cvt122
  • Peer Reviewed
• [Journal Article] Cardiac nuclear High Mobility Group Box 1 prevents the development of cardiac hypertrophy and heart failure. (2013)
  • Author(s): Funayama A, Shishido T, Netsu S, Narumi T, Kadowaki S, Takahashi H, Miyamoto T, Watanabe T, Woo CH, Abe JI, Kuwahara K, Nakao K, Takeishi Y, Kubota I.
  • Journal Title: Cardiovasc Res. Volume: 99 Issue: 4 Pages: 657-64
  • DOI: 10.1093/cvr/cvt128
  • Peer Reviewed
• [Journal Article] Circulating heart-type fatty acid binding protein levels predict the occurrence of appropriate shocks and cardiac death in patients with implantable cardioverter-defibrillators. (2012)
  • Author(s): Daidoji H, Arimoto T, Nitobe J, Tamura H, Kutsuzawa D, Ishigaki D, Ishino M, Takahashi H, Shishido T, Miyashita T, Miyamoto T, Watanabe T, Kubota I
  • Journal Title: J Card Fail. Volume: 18 Issue: 7 Pages: 564-569
  • DOI: 10.1016/j.cardfail.2012.04.006
  • Peer Reviewed
• [Journal Article] Impact of insulin resistance on silent and ongoing myocardial damage in normal subjects: the Takahata study. (2012)
  • Author(s): Narumi T, Shishido T, Kiribayashi N, Kadowaki S, Nishiyama S, Takahashi H, Arimoto T, Miyashita T, Miyamoto T, Watanabe T, Shibata Y, Konta T, Ueno Y, Kato T, Kayama T, Kubota I.
  • Journal Title: Diabetes Res. Volume: 2012 Pages: 815098-815098
  • DOI: 10.1155/2012/815098
  • Peer Reviewed
• [Presentation] Serum Uric Acid Lvels are Associated with Myocardial Damage in General Population (2014)
  • Author(s): Kadowaki S, Shishido T, Narumi T, Otaki Y, Honda Y, Wanezaki M, Nishiyama S, Arimoto T, Takahashi H, Miyamoto T, Watanabe T, Kubota I
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Association between Emotional Stress Evaluated by Levels of BDNF and the Exacebaiton of Chronic Heart Failure (2014)
  • Author(s): Kadowaki S, Shishido T, Kinoshita D, Yokoyama M, Narumi T, Otaki Y, Honda Y, Arimoto T, Takahashi H, Miyashita T, Miyamoto T, Watanabe T, Kubota I
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Cardiac-specific Overexpression of High-mobility Group Box 1 as a Novel Therapeutic Approach for Doxorubicin Cardiomyopathy (2014)
  • Author(s): Narumi T, Shishido T, Funayama A, Kadowaki S, Yokoyama M, Kinoshita D, Ohtaki Y, Honda Y, Nishiyama S, Takahashi H, Arimoto T, Miyashita T, Miyamoto T, Watanabe T, Kubota I
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Cardiac-specific overexpression of high-mobility group box 1 attenuates cardiovascular apoptosis and mitochondrial dysfunction during the pathogenesis of doxorubicin cardiomyopathy (2013)
  • Author(s): Narumi T, Kubota I et al.
  • Organizer: American Heart Association Scientific Sessions 2013, Dallas
  • Place of Presentation: USA, (Dallas Convention Center)
• [Presentation] Relationship Between Uric Acid and Myocardial Damage in General Population (2013)
  • Author(s): Shinpei Kadowaki, Tetsuro Shishido, Taro Narumi, Yuki Honda, Yoichiro Otaki, Masahiro Wanezaki, Satoshi Nishiyama, Takanori Arimoto, Hiroki Takahashi, Takuya Miyamoto, Takehiko Miyashita, Tetsu Watanabe, Isao Kubota
  • Organizer: アメリカ心臓協会学術集会
  • Place of Presentation: ダラスコンベンションセンター（米国 ダラス）
• [Presentation] Cardiac-specific Overexpression of High-mobility Group Box 1 Attenuates Cardiomyocyte Apoptosis and Mitochondrial Dysfunction During the Pathogenesis of Doxorubicin Cardiomyopathy (2013)
  • Author(s): Taro Narumi, Tetsuro Shishido, Akira Funayama, Miyuki Yokoyama, Daisuke Kinoshita, Shinpei Kadowaki, Yuki Honda, Yoichiro Otaki, Satoshi Nishiyama, Hiroki Takahashi, Takanori Arimoto, Takehiko Miyashita, Takuya Miyamoto, Tetsu Watanabe, Isao Kubota,
  • Organizer: アメリカ心臓協会学術集会
  • Place of Presentation: ダラスコンベンションセンター（米国 ダラス）
• [Presentation] Multple kidney biomarkers can risk-stratify chronic heart failure patients (2012)
  • Author(s): Kadowaki S, Shishido T, Narumi T, Kubota I et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles USA, (Los Angeles Convention Center)
• [Presentation] Left atrial ejection franction is a feasible parameter to predict poor prognosis in patients with heart failure and sinus rhythm (2012)
  • Author(s): Sasaki S, Tamura H, Watanabe T, Kubota I et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles USA, (Los Angeles Convention Center)
• [Presentation] Combination of iodine-123-meta- iodobenzylguanidine imaging and heart-type fatty acid binding protein for risk stratification in heart failure with preserved ejection fraction (2012)
  • Author(s): Katoh S, Shishido T, Arimoto T, Kubota I et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles USA, (Los Angeles Convention Center)
• [Presentation] Cardiac-specific overexpression of high-mobility group box 1 protects cardiomyocyte from apoptosis during the pathogenesis of doxorubicin cardiomyopathy (2012)
  • Author(s): Narumi T, Shishido T, Kadowaki S, Kubota I et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles USA, (Los Angeles Convention Center)
• [Presentation] Cardiac-specific overexpression of high-mobility group box 1 protects cardiomyocyte from apoptosis during the pathogenesis of doxorubicin cardiomyopathy. (2012)
  • Author(s): Funayama A, Shishido T, Ishino M, Ohtaki Y, Netsu S, Hasegawa H, Honda S, Kadowaki S, Narumi T, Nishiyama S, Arimoto T, Takiahashi H, Miyashita T, Miyamoto T, Watanabe T, Kubota I
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: ﾛｻﾝｾﾞﾙｽｺﾝﾍﾞﾝｼｮﾝｾﾝﾀｰ (ｶﾘﾌｫﾙﾆｱ､ｱﾒﾘｶ)
• [Presentation] Cardiac nuclear high mobility group box 1 attenuates cardiac dysfunction induced by pressure overload. (2012)
  • Author(s): Funayama A, Shishido T, Watanabe T, Kubota I
  • Organizer: 第29回国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: 九州大学医学部百年講堂 (福岡県)
• [Book] 循環器疾患最新の治療 (2014)
  • Author(s): 渡邉哲,久保田功
  • Total Pages: 528
  • Publisher: 南江堂
• [Book] 循環器疾患最新の治療 (2014)
  • Author(s): 渡邉哲，久保田功
  • Total Pages: 528
  • Publisher: 南江堂
• [Remarks] 山形大学医学部 内科学第一講座 （循環 ・呼吸・腎臓内科学分野）
  • URL: http://www.ichinai.com/