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Roles of connexin-43 in cardiomyocyte tolerance against ischemic injury

Research Project

Project/Area Number 18590781
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

MIURA Tetsuji  Sapporo Medical University, 2^<nd> Dept. of Internal Medicine, Associate Professor (90199951)

Co-Investigator(Kenkyū-buntansha) MIKI Takayuki  Sapporo Medical University, 2^<nd> Dept. of Internal Medicine, Assistant Professor (00336405)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,820,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsconnexin43 / gap junction / cell death / signal transduction / protein kinase / ischemic injury / preconditioning / コネキシン / 細胞情報伝達 / シグナル伝達 / 心筋細胞
Research Abstract

Myocardial ischemia induced complex formation of gap junction connexin-43 (Cx43) with Src, PKC-ε and p38MAPK-α in rat hearts. Ischemic preconditioning (PC) did not modify Cx34-Src interaction during ischemia but significantly increased binding of Cx43 with PKC-ε. PC suppressed Cx43-p38MAPK binding and p38MAPK activity in the Cx43 immunoprecipitates. Gap junction permeability assessed by Lucifer yellow was significantly suppressed by PC, and this effect of PC was abolished by inhibition of PKC-ε. In contrast, inhibition of p38MAPK modestly increased gap junction permeability during myocardial ischemia. Contribution of suppressed gap junction permeability to myocardial salvage was assessed by activation of the δ-opioid receptor, which is one of receptors responsible for triggering PC mechanisms. A δ-opioid receptor agonist, DADLE, mimicked the effect of PC on gap junction permeability and infarct size, and elimination of its effect on gap junction by a PKC-ε inhibitor attenuated infarct … More size-limiting effect of DADLE by 35%. In cardiomyocyte cell line (H9c2 cell), activation of the δ-opioid receptor, or the IGF receptor induces phosphorylation of Akt and GSK-3β and afford cytoprotection against oxidant stress-induced cell necrosis. Suppression of Cx43 expression by use of its siRNA abolished both PI3K-Akt-GSK-3β signaling and cytoprotection induced by a δ-opioid receptor agonist. However, Akt and GSK-3β phosphorylation and cytoprotection against necrosis by IGF-1 were preserved even after knock-down of Cx43. The results of the present study indicate that Cx43 plays two, at least, important roles as a determinant of myocardial tolerance against ischemia/reperfusion injury. First, gap junction Cx43 is a target of PC mechanisms which suppress propagation of cell injury via the gap junction. PKC-ε and p38MAPKα are a primary inhibitory factor and a counter-acting modulation factor, respectively, of the gap junction regulation by PC. Second, Cx43 plays a crucial role in transmission of cytoprotective PI3K-Akt-GSK-3β signaling from activated G-protein coupled receptors. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (31 results)

All 2009 2008 2007 2006 2005

All Journal Article (12 results) (of which Peer Reviewed: 7 results) Presentation (19 results)

  • [Journal Article] Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning2009

    • Author(s)
      Kazuyuki Naitoh, et al.
    • Journal Title

      American Journal of Physiology 296

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Roles of Cx43-assocaited protein kinases in sup- pression of gap junction-mediated chemical coupling by ischemic pre- conditioning.2009

    • Author(s)
      Kazuyuki Naitoh, et al.
    • Journal Title

      American Journal of Physiology 296

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Ser9 phosphorylation of mitochondrial GSK-3βis a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis2008

    • Author(s)
      Katsuhiko Ohori, et al.
    • Journal Title

      American Journal of Physiology 295

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Ser9 phosphorylation of mitochondrial GSK-3βis a primary mechanism of cardiomyocyte protection by erythropoietin against oxidantinduced apoptosis2008

    • Author(s)
      Katuhiko Ohori, et al.
    • Journal Title

      American Journal of Physiology 295

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion.2008

    • Author(s)
      Hironori Kobayashi
    • Journal Title

      Clinical and Experimental Pharmacology and Physiology 35

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorvlation of connexin 43.2007

    • Author(s)
      Tetsuji Miura, et al.
    • Journal Title

      American Journal of Physiology 293

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Modulation of the mitochondrial penneability transition pore complex in GSK-3β-mediated myocardial protection.2007

    • Author(s)
      Masahiro Nishihara, et al.
    • Journal Title

      Journal of Molecular and Cellular Cardiology 43

      Pages: 564-570

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKOe-mediated phos phorylation of connexin432007

    • Author(s)
      Tetsuji Miura, et al.
    • Journal Title

      American Journal of Physiology 293

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Modulation of the mitochondrial permeability Transition pore complex in GSK-3β-mediated myocardial protectio2007

    • Author(s)
      Masahiro Nishihara, et al.
    • Journal Title

      Journal of Molecular and Cellular Cardiology 43

      Pages: 564-570

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Delta-opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-epsilon-mediated phosphorylation of connexin 432007

    • Author(s)
      Tetsuji Miura
    • Journal Title

      American Journal of Physiology 293

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection.2007

    • Author(s)
      Masahiro Nishihara
    • Journal Title

      Journal of Molecular and Cellular Cardiology 43

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ischemic preconditioning, an endogenous protective mechanism in the cardiomyocyte, and its clinical application2006

    • Author(s)
      Tetsuji Miura, et al.
    • Journal Title

      Sapporo Medical Journal 75・4-6

      Pages: 19-28

    • NAID

      120001795140

    • Related Report
      2006 Annual Research Report
  • [Presentation] ER stress contributes to dysregulation of GSK-3β-medaited suppression of mitochondrial permeability transition in diabetic hearts.2008

    • Author(s)
      Takayuki Miki, et al.
    • Organizer
      81^<st> Scientific Sessions of American Heart Association
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2008-11-09
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Connexm-43 contributes to pro-survival Akt/GSK-3β signaling and cardioniyocte protection in a receptor-specific manner.2008

    • Author(s)
      Satoko Ishikawa, et al.
    • Organizer
      第72回日本循環器学会
    • Place of Presentation
      福岡
    • Year and Date
      2008-03-29
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Connexin-43 contributed to pro-survival Akt/GSK-3β signaling and cardiomyocyte protection in a receptor-specific manner.2008

    • Author(s)
      Satoko Ishikawa, et al.
    • Organizer
      72^<nd> Scientific Meeting of the Japanese Circulation Society
    • Place of Presentation
      Fukuoka, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] ES stress contributes to dysregulation of GSK-3β-medaited suppression of mitochondrial permeability transition in diabetic hearts.2008

    • Author(s)
      Takayuki Miki, et al.
    • Organizer
      81^<st> Scientific Sessions of American Heart Association
    • Place of Presentation
      New Orleans, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Suppression of GSK-3β activity by its Ser9-phosphorylation contributes to cardiomyocyte protection afforded by erythropoietin against oxidative stress-induced apoptosis.2007

    • Author(s)
      Katushiko Ohori, et al.
    • Organizer
      80^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Orlando, USA
    • Year and Date
      2007-11-06
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Modification of Akt/GSK-3b signaling and mitochondrial GSK-3β by ER stress underlies failure of erythropoietin to protect diabetic hearts.2007

    • Author(s)
      Takayuki Miki
    • Organizer
      American Heart Association Scientific Sessions 2007
    • Place of Presentation
      Orlando, Florida, USA
    • Year and Date
      2007-11-06
    • Related Report
      2007 Annual Research Report
  • [Presentation] Modulation of Akt/GSK-3β signaling and mitochondrial GSK-3βby ER stress underlies failure of erythropoietin to protect diabetic hearts.2007

    • Author(s)
      Takayuki Miki, et al.
    • Organizer
      80^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Orlando, USA
    • Year and Date
      2007-11-05
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Suppression of mitochondrial GSK-3β activity by its Ser9-phosphorylation contri-butes to cardiomyocyte protection afforded by erythropoietin against oxidative st-ress-induced apoptosis2007

    • Author(s)
      Katsuhiko Ohori
    • Organizer
      American Heart Association Scientific Sessions 2007
    • Place of Presentation
      Orlando, Florida, USA
    • Year and Date
      2007-11-05
    • Related Report
      2007 Annual Research Report
  • [Presentation] Erythropoietin inhibits cardiomyocyte apoptosis through inactivation of glycogen svnthase kmase-3β.2007

    • Author(s)
      Katsuhiko Ohori, et al.
    • Organizer
      19^<th> World Congress of the International Society for Heart Research
    • Place of Presentation
      Bologna, Italy
    • Year and Date
      2007-06-24
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Roles of p38MAPK and PKC in connexin43-mediated gap junction modulation by ischemic preconditioning.2007

    • Author(s)
      Tetsuji Miura, et al.
    • Organizer
      19^<th> World Congress of the International Society for Heart Research
    • Place of Presentation
      Bologna, Italy
    • Year and Date
      2007-06-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Modulation of mitochondrial permeability transition pore complex in GSK-3β-mediated cardiomyocyte protection.2007

    • Author(s)
      Masahiro Nishihara, et al.
    • Organizer
      第71回日本循環器学会
    • Place of Presentation
      神戸
    • Year and Date
      2007-03-15
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Modulation of mitochondrial permeability transition pore complex in GSK-3β-mediated cardiomyocyte protection.2007

    • Author(s)
      Masahiro Nishihara, et al
    • Organizer
      71^<st> Annual Scientific Meeting of the Japanese Circulation Society
    • Place of Presentation
      Kobe, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Erythropoietin inhibits cardiomyocyte apoptosis through inactivation of glycogen synthase kinase-3β.2007

    • Author(s)
      Katsuhiko Ohori, et al.
    • Organizer
      19^<th> World Congress of the International Society for Heart Keseareh
    • Place of Presentation
      Bologna, Italy
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Roles of p38MAPK and PKC in connexin43-mediated gap junction modulation by ischemic preconditioning.2007

    • Author(s)
      Tetsuji Miura, et al.
    • Organizer
      19^<th> World Congress of the International Society for Heart Keseareh
    • Place of Presentation
      Bologna, Italy
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Modulation of Akt/GSK-3β signaling and mitochondrial GSK-3β by ER stress underlies failure of erythropoietin to protect diabetic hea2007

    • Author(s)
      Takayuki Miki, et al.
    • Organizer
      80^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Orlando, USA.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Suppression of GSK-3β activity by its Ser9-phosphorylation contributes to cardiomyocyte protection afforded by erythropoietin against oxidative stress-induced apoptosis.2007

    • Author(s)
      Katushiko Ohori, et al.
    • Organizer
      80^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Orlando, USA.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Contribution of gap junction-dependent and -independent mechanisms to myocardialsalvage by δ-opioid receptor activation.2006

    • Author(s)
      Kazuyuki Naitoh, et al.
    • Organizer
      79^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Chicago, USA
    • Year and Date
      2006-11-14
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Contribution of gap junction"dependent and in dependent mechanisms to myocardial salvage by δ-opioid receptor activation.2006

    • Author(s)
      Kazuyuki Naitoh, et al.
    • Organizer
      79^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Chicago, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] GSK-3β signaling module in mitochondria leading to myocardial protection against infarction.2005

    • Author(s)
      Masahiro Nishihara, et al.
    • Organizer
      79^<th> Scientific Sessions of American Heart Association
    • Place of Presentation
      Chicago, USA
    • Year and Date
      2005-11-15
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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