Source:http://linkedlifedata.com/resource/pubmed/id/12829618
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
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| pubmed:dateCreated |
2003-8-8
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| pubmed:abstractText |
The ischemic activation of p38alpha mitogen-activated protein kinase (p38alpha-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- murine heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3+/+ mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50+/-5 versus 51+/-4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608+/-224 versus 384+/-104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127+/-23 versus 540+/-267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 micromol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143+/-2 versus 436+/-96, P=0.003, and 122+/-25 versus 623+/-176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57+/-5 versus 36+/-3, P<0.001, and 50+/-5 versus 29+/-3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38alpha-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 micromol/L) did not prevent the phosphorylation of resistant p38alpha-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Map2k3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/SB 203580,
http://linkedlifedata.com/resource/pubmed/chemical/TAB1 protein, MAPKKK activator...,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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| pubmed:issn |
1524-4571
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
8
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| pubmed:volume |
93
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
254-61
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:12829618-Animals,
pubmed-meshheading:12829618-Carrier Proteins,
pubmed-meshheading:12829618-Cells, Cultured,
pubmed-meshheading:12829618-Disease Progression,
pubmed-meshheading:12829618-Enzyme Activation,
pubmed-meshheading:12829618-Enzyme Inhibitors,
pubmed-meshheading:12829618-Imidazoles,
pubmed-meshheading:12829618-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:12829618-MAP Kinase Kinase 3,
pubmed-meshheading:12829618-MAP Kinase Signaling System,
pubmed-meshheading:12829618-Male,
pubmed-meshheading:12829618-Mice,
pubmed-meshheading:12829618-Mice, Inbred C57BL,
pubmed-meshheading:12829618-Mice, Knockout,
pubmed-meshheading:12829618-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:12829618-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12829618-Myoblasts,
pubmed-meshheading:12829618-Myocardial Infarction,
pubmed-meshheading:12829618-Myocardial Ischemia,
pubmed-meshheading:12829618-Phosphorylation,
pubmed-meshheading:12829618-Protein-Tyrosine Kinases,
pubmed-meshheading:12829618-Pyridines,
pubmed-meshheading:12829618-Signal Transduction,
pubmed-meshheading:12829618-Transfection,
pubmed-meshheading:12829618-Tumor Necrosis Factor-alpha,
pubmed-meshheading:12829618-p38 Mitogen-Activated Protein Kinases
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| pubmed:year |
2003
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| pubmed:articleTitle |
Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia.
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| pubmed:affiliation |
Department of Cardiology, Guy's, King's and St Thomas' School of Medicine, King's College London, The Rayne Institute, St Thomas' Hospital, London, UK.
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| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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