Intracellular Signaling Mechanisms Regulating Functions and Expression of the Gap Junction in Ischemic Myocardium
| Project/Area Number |
16590702
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
MIURA Tetsuji Sapporo Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (90199951)
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| Co-Investigator(Kenkyū-buntansha) |
MIKI Takayuki Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (00336405)
SAKAMOTO Jun Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (40336392)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | gap junction / connexin / ischemia / mitochondria / protein kinase / preconditioning / signal transduction / myocardial infarction / protein kinase C / MAP kinase / ATP-sensitive K+ channel / ATP-sensitive potassium channel |
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| Research Abstract |
We have previously found that ischemic preconditioning (IPC) accelerates closure of the gap junction in ischemic myocardium, which contributes to cardioprotection afforded by IPC. In this study, we aimed to clarify roles of the mitochondrial ATP-sensitive potassium channel (mK_<ATP> ch) and protein kinase C (PKC) in IPC-induced suppression of gap junction permeability in ischemic myocardium. A selective opener of the mK_<ATP> ch, diazoxide, activated ERK1/2 by free radical dependent mechanism, whereas PKC-ε was not activated by diazoxide. After treatment with diazoxide, myocardial ERK1/2 was phosphorylated and co-immunoprecipitated with connexin-43, and the level of phospho-Ser279/Ser282-conenxin43 was significantly elevated. Suppression of gap junction permeability by diazoxide was inhibited by an ERK inhibitor, PD98059. In the second series of experiments, 8-opioid receptor, a trigger receptor in IPC, in the myocardium was activated by its selective agonist, DADLE. DADLE suppressed g
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ap junction permeability in ischemic myocardium, which was sensitive to a non-selective PKC inhibitor (calphostin C) and a PKC-ε selective inhibitory peptide. Activation of the 8-opioid receptor induced translocation of PKC-ε to the intercalated disc, binding to connexin43 and phosphorylation of Ser368 of connexin43. These results indicate that there are two, at least, mechanisms by which IPC suppresses gap junction permeability; one is activation of PKC-ε and PKC-ε-mediated phosphorylation of connexin43 and the other is phosphorylation of connexin43 by ERK that is activated by free radicals generated by opening of the mKATP ch. Suppression of the gap junction permeability, which inhibits propagation of myocyte injury within ischemic/reperfused myocardium, appears to explain approximately 30% of infarct size-limiting effect of IPC, since this extent of cardioprotection by DADLE was eliminated by inhibitors of PKC-s.
In this project, we also characterized infarct repair process to get an insight into cytokines and interstial cells that possibly influence connexin expression in myocyte at infarct border zones. Less
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Report
(3 results)
Research Products
(13 results)
