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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
32
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pubmed:dateCreated |
2003-8-4
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pubmed:abstractText |
Cytochrome P450-derived epoxyeicosatrienoic acids (EETs) stimulate endothelial cell proliferation and angiogenesis. In this study, we investigated the involvement of the forkhead box, class O (FOXO) family of transcription factors and their downstream target p27Kip1 in EET-induced endothelial cell proliferation. Incubation of human umbilical vein endothelial cells with 11,12-EET induced a time- and dose-dependent decrease in p27Kip1 protein expression, whereas p21Cip1 was not significantly affected. This effect on p27Kip1 protein was associated with decreased mRNA levels as well as p27Kip1 promoter activity. 11,12-EET also stimulated the time-dependent phosphorylation of Akt and of the forkhead factors FOXO1 and FOXO3a, effects prevented by the phosphatidylinositol 3-kinase inhibitor LY 294002. Transfection of endothelial cells with either a dominant-negative or an "Akt-resistant"/constitutively active FOXO3a mutant reversed the 11,12-EET-induced down-regulation of p27Kip1, whereas transfection of a constitutive active Akt decreased p27Kip1 expression independently of the presence or absence of 11,12-EET. To determine whether these effects are involved in EET-induced proliferation, endothelial cells were transfected with the 11,12-EET-generating epoxygenase CYP2C9. Transfection of CYP2C9 elicited endothelial cell proliferation and this effect was inhibited in cells co-transfected with CYP2C9 and either a dominant-negative Akt or constitutively active FOXO3a. Reducing FOXO expression using RNA interference, on the other hand, attenuated p27Kip1 expression and stimulated endothelial cell proliferation. These results indicate that EET-induced endothelial cell proliferation is associated with the phosphatidylinositol 3-kinase/Akt-dependent phosphorylation and inactivation of FOXO factors and the subsequent decrease in expression of the cyclin-dependent kinase inhibitor p27Kip1.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/11,12-epoxy-5,8,14-eicosatrienoic...,
http://linkedlifedata.com/resource/pubmed/chemical/8,11,14-Eicosatrienoic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases,
http://linkedlifedata.com/resource/pubmed/chemical/CYP2C9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/FOXO1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Forkhead Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Vasodilator Agents
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
8
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
29619-25
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:12773534-8,11,14-Eicosatrienoic Acid,
pubmed-meshheading:12773534-Aryl Hydrocarbon Hydroxylases,
pubmed-meshheading:12773534-Blotting, Northern,
pubmed-meshheading:12773534-Blotting, Western,
pubmed-meshheading:12773534-Cell Cycle Proteins,
pubmed-meshheading:12773534-Cell Division,
pubmed-meshheading:12773534-Cells, Cultured,
pubmed-meshheading:12773534-Cyclin-Dependent Kinase Inhibitor p27,
pubmed-meshheading:12773534-DNA-Binding Proteins,
pubmed-meshheading:12773534-Dose-Response Relationship, Drug,
pubmed-meshheading:12773534-Down-Regulation,
pubmed-meshheading:12773534-Endothelium, Vascular,
pubmed-meshheading:12773534-Enzyme Inhibitors,
pubmed-meshheading:12773534-Forkhead Transcription Factors,
pubmed-meshheading:12773534-Genes, Dominant,
pubmed-meshheading:12773534-Humans,
pubmed-meshheading:12773534-Immunoblotting,
pubmed-meshheading:12773534-Luciferases,
pubmed-meshheading:12773534-Neovascularization, Physiologic,
pubmed-meshheading:12773534-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:12773534-Phosphorylation,
pubmed-meshheading:12773534-Plasmids,
pubmed-meshheading:12773534-Promoter Regions, Genetic,
pubmed-meshheading:12773534-RNA, Messenger,
pubmed-meshheading:12773534-RNA, Small Interfering,
pubmed-meshheading:12773534-Time Factors,
pubmed-meshheading:12773534-Transcription Factors,
pubmed-meshheading:12773534-Transfection,
pubmed-meshheading:12773534-Tumor Suppressor Proteins,
pubmed-meshheading:12773534-Umbilical Veins,
pubmed-meshheading:12773534-Vasodilator Agents
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pubmed:year |
2003
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pubmed:articleTitle |
11,12-Epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating p27Kip1.
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pubmed:affiliation |
Institut für Kardiovaskuläre Physiologie, Klinikum der J. W. G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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