2003 Fiscal Year Final Research Report Summary
FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury.
| Project/Area Number |
14370408
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Thoracic surgery
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| Research Institution | Mie University |
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Principal Investigator |
YADA Isao Mie University, Faculty of medicine, Professor, 医学部, 教授 (80093152)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAO Motoshi Mie University, Faculty of medicine, Research Associate, 医学部, 助手 (30263007)
ONODA Koji Mie University, Hospital, Assistant Professor, 医学部附属病院, 講師 (70260601)
SHIMPO Hideto Mie University, Faculty of medicine, Associate Professor, 医学部, 助教授 (70179076)
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| Project Period (FY) |
2002 – 2003
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| Keywords | ischemia-reperfusion injury / toll-like receptor 4 / extracellular signal-regulated kinase / mitogen-activated protein kinase / activating transcription factor-2 / inflammatory cytokines |
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| Research Abstract |
P38 mitogen-activated protein kinase (MAPK) is activated during myocardial ischemia-reperfusion (MI/R) injury. we examined the effect of a highly specific inhibitor of p38 MAPK, FR167653, in an experimental model of regional MI/R.
<Method> : CD-1 mice received Fr167653 intraperitoneally 24 hours prior to 30 minutes of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. P38 MAPK activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 MAPK or its substrate, activating transcription factor -2. Nuclear factor (NF) -kB activity was measured by detecting translocation of NF-kB to the nucleus. The expression of inframmatory cytokines was measured by ribonuclease protection assay.
<Results> : Pretreatment of mice with FR167653 before MI/R resulted in reduction in p38 MAPK phosphorylation (p=.018), inhibition of p38 MAPK activity (p.047), less nulear of NF-kB(P=.001), and a decrease in the expression of inflammatory cytokiness (tumor necrosis factor-a : p=.023, ;interleukine01b : p=.038 ; mynocyte chemotacic protein-1 : p=.001) in the heart and the development of a significantly smaller infarct(p=.0069), when comared to hearts from mice trasted with vehicle aone. Activation of c-Jun NH2-terminal kinase and extracellular signa-regulated kinase were observed after MI/R, while not inhibited by FR167653
<Conclusion> : we conclude that FR167653 selectively inhibits p38 MAPK activation and activity during regional MI/R injury and efficaciously reduces infarct size (by 73.6%). Thus, p38 MAPK inhibition may have a role in the treatment of MI/R
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