• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Development of molecular therapy correcting abnormal intracellular Ca^<2+> regulation in chronic heart failure

Research Project

Project/Area Number 16209026
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionYamaguchi University

Principal Investigator

MATSUZAKI Masunori  Yamaguchi University, Graduate school of Medicine, Professor, 大学院医学系研究科, 教授 (60116754)

Co-Investigator(Kenkyū-buntansha) YANO Masafumi  Yamaguchi University, Hospital, Assistant professor, 医学部附属病院, 講師 (90294628)
IKEDA Yasuhiro  Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00260349)
AOKI Hiroki  Yamaguchi University School of Medicine, School of Medicine, Associate Professor, 医学部, 助教授 (60322244)
KIMURA Yoshihiro  Yamaguchi University, Graduate school of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (90301308)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥43,420,000 (Direct Cost: ¥33,400,000、Indirect Cost: ¥10,020,000)
Fiscal Year 2006: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Fiscal Year 2005: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2004: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000)
Keywordsgene delivery / heart failure / sarcoplasmic reticulum / calcium handling / molecular therapy / 筋小胞体 / カルシウムイオン / 分子標的療法 / 慢性心不全 / 拡張型心筋症 / リアノジン受容体 / ドメイン相関 / 蛋白ホスファターゼ1 / 心筋症ハムスター / 高効率生体内遺伝子導入 / Inhibitor-2 / アデノウイルスベクター / アデノ随伴ウイルスベクター / 高効率生体内心筋遺伝子導入 / RyRドメインペプチド
Research Abstract

An abnormal regulation of intracellular Ca^<2+> by sarcoplasmic reticulum has been shown to be involved in the mechanism underlying contractile and relaxation dysfunction in heart failure. We investigated molecular targeting strategies of correcting the abnormal calcium regulation either via the ryanodine receptor (RyR) or via the SR calcium ATPase (SERCA) /phospholamban (PLN) complex in chronic heart failure. In RyR, we have found that a single amino acid mutation seen in the patient with arrhythmogenic right ventricular dysplasia can trigger abnormal domain interaction between amino-terminal and central peptide domain, leading to abnormal SR calcium leak and subsequent fetal arrhythmia. The same conformational change was observed in the failing heart, suggesting the similar arrhythmogenic mechanism. In addition, this kind of calcium leak is also triggered by the increased production of reactive oxygen species (ROS) in the failing heart. Therfore, reduction of ROS could be a novel str … More ategy to prevent fetal arrhythmia in heart failure Furthermore we also found that a classical medicine for malignant hyperthermia, dantrolene, can interfere with these abnormal conformational changes in RyR, thereby potentially correcting impaired calcium cycling in the failing heart.
On the other hand, calcium uptake function via SERCA pump and phospholamban in the network SR is also impaired in the failing heart. This has in part been attributed to the decreased levels of pholpholamban phosphorylation at Ser 16, possibly caused by the increased protein phosphatase 1 (PP1) activity in the failing heart. We have attempted to correct this abnormal increase in PP1 activity. Using in vivo high efficiency gene delivery technique, we have introduced an endogenous constitutive PP1 inhibitor, inhibitor-2, into the cardiomyopathic hamster heart. Inhibitor-2 gene delivery not only rescued the cardiac finction but also ameliorated BNP expression, cardiac fibrosis and extended the consequent survival time.
In summary, molecular targeting strategy in RyR or SERCA/PLN complex and associated PP1 could be a good therapeutic target for heart failure. Less

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (55 results)

All 2007 2006 2005 2004

All Journal Article (51 results) Book (4 results)

  • [Journal Article] Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure.2007

    • Author(s)
      Mochizuki M et al.
    • Journal Title

      J Am Coll Cardiol. 49(16)

      Pages: 1722-1732

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Progression of heart failure was suppressed by inhibition of apoptosis-signal regulating kinase 1(ASK-1) via transcoronary gene transfer2007

    • Author(s)
      Shungo Hikoso, et al.
    • Journal Title

      J Am Coll Cardiol (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Progression of heart failure was suppressed by inhibition of apoptosis-signal regulating kinase 1(ASK-1) via transcoronary gem transfer2007

    • Author(s)
      Hikoso S, et al.
    • Journal Title

      J Am Coll Cardiol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Scavenging free radicals by low-dose carvedilol prevent : redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure.2007

    • Author(s)
      Mochizuki M, et al.
    • Journal Title

      J Am Coll Cardiol. 49(16)(Epub 2007 Apr 5)

      Pages: 1722-32

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure.2007

    • Author(s)
      Manoru Mochizuki
    • Journal Title

      J Am Coll Cardiol 49(16)

      Pages: 1722-32

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy.2006

    • Author(s)
      Yamada M et al.
    • Journal Title

      FASEB J. 20(8)

      Pages: 1197-1199

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Pleiotropic Effects of the beta-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes.2006

    • Author(s)
      Wang R et al.
    • Journal Title

      J Pharmacol Exp Ther. 318(1)

      Pages: 45-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes.2006

    • Author(s)
      Maruyama R et al.
    • Journal Title

      Am J Physiol Heart Circ Physiol. 290(4)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mechanisms of Disease : ryanodine receptor defects in heart failure and fatal arrhythmia.2006

    • Author(s)
      Yano M et al.
    • Journal Title

      Nature Clinical Practice Cardiovascular Medicine 3

      Pages: 43-43

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.2006

    • Author(s)
      Yoshimura K et al.
    • Journal Title

      Ann N Y Acad Sci. 1085

      Pages: 403-406

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.2006

    • Author(s)
      Yoshimura K et al.
    • Journal Title

      Ann N Y Acad Sci. 1085

      Pages: 74-81

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cytokines Produced by Bone Marrow Cells can Contribute to Functional Improvement of the Infarcted Heart by Protecting Cardiomyocytes from Ischemic Injury.2006

    • Author(s)
      Takahashi M et al.
    • Journal Title

      Am J Physiol Heart Circ Physiol. 291(2)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] High ambient pressure produces hypertrophy and up-regulates cardiac sarc oplasmic reticulum Ca2+ regulatory proteins in cultured rat cardiomyocytes.2006

    • Author(s)
      Sato T, et al.
    • Journal Title

      Hypertens Res. 29

      Pages: 1013-1020

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] AT1 receptor antagonist restores cardiac ryanodine receptor function, rend ering isoproterenol-induced failing heart less susceptible to Ca2+ -leak in duced by oxidative stress.2006

    • Author(s)
      Tokuhisa T, et al.
    • Journal Title

      Circ J 70

      Pages: 777-786

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.2006

    • Author(s)
      Yoshimura K, et al.
    • Journal Title

      Ann N Y Acad Sci. Nov;1085

      Pages: 403-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.2006

    • Author(s)
      Yoshimura K, et al.
    • Journal Title

      Ann N Y Acad Sci. Nov;1085

      Pages: 74-81

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] AT1 receptor antagonist restores cardiac ryanodine receptor function rendering isoproterenol-induced failing heart less susceptible to Ca2+ -leak induced by oxidative stress.2006

    • Author(s)
      Tokuhisa T, et al.
    • Journal Title

      Circ J. 70(6)

      Pages: 777-86

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Inhibition of protein phosphatase 1 by inhibitor-2 gene deliver) ameliorates heart failure progression in genetic cardiomyopathy.2006

    • Author(s)
      Yamada M, et al.
    • Journal Title

      FASEB J. 20(8)(Epub 2006 Apr 20)

      Pages: 1197-9

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Pleiotropic effects of the beta-adrenoceptor blocker carvedilol on calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes2006

    • Author(s)
      Wang R, et al.
    • Journal Title

      J Pharmacol Exp Ther. 318(1)(Epub 2006 Apr 12)

      Pages: 45-52

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury.2006

    • Author(s)
      Takahashi M, et al.
    • Journal Title

      Am J Physiol Heart Circ Physiol. 291(2)(Epub 2006 Apr 7)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mechanisms of Disease : ryanodine receptor defects in heart failure and fatal arrhythmia.2006

    • Author(s)
      Yano M, et al.
    • Journal Title

      Nat Clin Pract Cardiovasc Med., Review. 3(l)

      Pages: 43-52

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes.2006

    • Author(s)
      Maruyama R, et al.
    • Journal Title

      Am J Physiol Heart Circ Physiol. 290(4)(Epub 2005 Nov 11)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] High ambient pressure produces hypertrophy and up-regulates cardiac sarcoplasmic reticulum Ca2+ regulatory proteins in cultured rat cardiomyocytes.2006

    • Author(s)
      Sato T, et al.
    • Journal Title

      Hypertens Res. 29(12)

      Pages: 1013-20

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy.2006

    • Author(s)
      Michio Yamada
    • Journal Title

      FASEB J. 20(8)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Plciotropic Effects of the beta-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes.2006

    • Author(s)
      Wang R
    • Journal Title

      J Pharmacol Exp Ther. 318(1)

      Pages: 45-52

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.2006

    • Author(s)
      Koichi Yoshimura
    • Journal Title

      Ann N Y Acad Sci. 1085

      Pages: 403-6

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.2006

    • Author(s)
      Koichi Yoshimura
    • Journal Title

      Ann N Y Acad Sci. 1085

      Pages: 74-81

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Inhibition of protein phosphates 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy2006

    • Author(s)
      Yamada M
    • Journal Title

      FASEB Journal (In print)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mechanisms of Disease : ryanodine receptor defects in heart failure and fatal arrhythmia.2006

    • Author(s)
      Yano M
    • Journal Title

      Nature Clinical Practice Cardiovascular Medicine 3

      Pages: 43-43

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Correction of defective interdomain interaction within ryanod ine receptor by antioxidant is a new therapeutic strategy aga inst heart failure.2005

    • Author(s)
      Yano M et al.
    • Journal Title

      Circulation 112

      Pages: 3633-3633

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.2005

    • Author(s)
      Yoshimura K
    • Journal Title

      Nature Medicine 11

      Pages: 1330-1330

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005

    • Author(s)
      Oda T et al.
    • Journal Title

      Circulation 111

      Pages: 3400-3400

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca2+-ATPase and modulates excitation-contraction coupling in the heart2005

    • Author(s)
      Matsumoto T et al.
    • Journal Title

      Bas Res Cardiol 100

      Pages: 250-250

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Altered intracellular Ca2+ handling in heart failure2005

    • Author(s)
      Yano Masafumi et al.
    • Journal Title

      J Clin Invest. 115

      Pages: 556-564

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure.2005

    • Author(s)
      Yano M, et al.
    • Journal Title

      Circulation. 112(23)

      Pages: 3633-43

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.2005

    • Author(s)
      Yoshimura K, et al.
    • Journal Title

      Nat Med. 11(12)(Epub 2005 Nov 27)

      Pages: 1330-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure.2005

    • Author(s)
      Oda T, et al.
    • Journal Title

      Circulation. 111(25)

      Pages: 3400-10

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure.2005

    • Author(s)
      Oda T, et al.
    • Journal Title

      Circulation. 112(17)(Epub 2005 Jun 20.Erratum)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Altered intracellular Ca2+ handling in heart failure.2005

    • Author(s)
      Yano M, et al.
    • Journal Title

      J Clin Invest., Review 115(3)

      Pages: 556-64

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca(2+)-ATPase and modulates excitation-contraction coupling in the heart.2005

    • Author(s)
      Matsumoto T, et al.
    • Journal Title

      Basic Res Cardiol. 100(3)(Epub 2005 Mar 9)

      Pages: 250-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure.2005

    • Author(s)
      Yano M
    • Journal Title

      Circulation 112

      Pages: 3633-3633

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005

    • Author(s)
      Oda T
    • Journal Title

      Circulation 111

      Pages: 3400-3400

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca2+-ATPase and modulates excitation-contraction coupling in the heart2005

    • Author(s)
      Matsumoto T
    • Journal Title

      Bas Res Cardiol 100

      Pages: 250-250

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Altered intracellular Ca2+ handling in heart failure2005

    • Author(s)
      Yano Masafumi, Yasuhiro Ikeda, Masunori Matsuzaki
    • Journal Title

      J Clin Invest. 115

      Pages: 556-564

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005

    • Author(s)
      Oda T et al.
    • Journal Title

      Circulation (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Sorcin interacts with sarcoplasmic reticulum Ca2+-ATPase and modulates excitation-contraction coupling in the heart2005

    • Author(s)
      Matsumoto T et al.
    • Journal Title

      Bas Res Cardiol (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] T-cap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy2004

    • Author(s)
      Hayashi T et al.
    • Journal Title

      J Am Coll Cardiol 44

      Pages: 2192-2201

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Rapid electrical stimulation of contraction modulates gap junction protein in neonatal rat cultured cardiomyocytes : involvement of mitogen-activated protein kinases and effects of angiotensin II-receptor antagonist.2004

    • Author(s)
      Inoue N, et al.
    • Journal Title

      J Am Coll Cardiol 44

      Pages: 914-922

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats.2004

    • Author(s)
      Iwanaga Y, et al.
    • Journal Title

      Clin Invest. 113(5)

      Pages: 727-36

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rapid electrical stimulation of contraction modulates gap junction protein in neonatal rat cultured cardiomyocytes : involvement of mitogen-activated protein kinases and effects of angiotensin II-receptor antagonist.2004

    • Author(s)
      Inoue N, et al.
    • Journal Title

      J Am Coll Cardiol. 44(4)

      Pages: 914-22

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Valsartan restores sarcoplasmic reticulum function with no appreciable effect on resting cardiac function in pacing-induced heart failure.2004

    • Author(s)
      Okuda Shinichi et al.
    • Journal Title

      Circulation 109

      Pages: 911-919

    • Related Report
      2004 Annual Research Report
  • [Book] Heart Failure Pathophysiology (Supportive Care for Cardiac Patient)2007

    • Author(s)
      Ikeda Y et al.
    • Publisher
      Oxford University Press (In press)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Heart Failure Pathophysiology (Supportive Care for Cardiac Patient)2007

    • Author(s)
      Yasuhiro Ikeda
    • Publisher
      Oxford University Press(In press)
    • Related Report
      2006 Annual Research Report
  • [Book] Molecular Mechanism of Heart Diseases Chapter 12 : Myocardial gene therapy as prototype prodrug delivery system for intractable heart failure2005

    • Author(s)
      Ikeda Y
    • Total Pages
      219
    • Publisher
      Research Signpost Inc.
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Molecular Mechanism of Heart Diseases Chapter 12 : Myocardial gene therapy as prototype prodrug delivery system for intractable heart failure2005

    • Author(s)
      Ikeda Y
    • Total Pages
      216
    • Publisher
      Research Signpost Inc.,
    • Related Report
      2005 Annual Research Report

URL: 

Published: 2004-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi