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

2013 Fiscal Year Final Research Report

• 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
• Keywords: 慢性心不全 / 胎児型遺伝子 / アセチル化

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] 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 Pages: e53133
  • Peer Reviewed
• [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)
  • Year and Date: 20131116-20
• [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)
  • Year and Date: 20121103-07
• [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)
  • Year and Date: 20121103-07
• [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)
  • Year and Date: 20121103-07
• [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)
  • Year and Date: 20121103-07
• [Book] 循環器疾患最新の治療 (2014)
  • Author(s): 渡邉哲,久保田功
  • Total Pages: 528 (424-426)
  • Publisher: 南江堂