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11,12-Epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating p27(Kip1)

Item Type:Article
Title:11,12-Epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating p27(Kip1)
Creators Name:Potente, M. and Fisslthaler, B. and Busse, R. and Fleming, I.
Abstract: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 p27(Kip1) 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 p27(Kip1) protein expression, whereas p21(Cip1) was not significantly affected. This effect on p27(Kip1) protein was associated with decreased mRNA levels as well as p27(Kip1) 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 p27(Kip1), whereas transfection of a constitutive active Akt decreased p27(Kip1) 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 p27(Kip1) 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 p27(Kip1).
Keywords:8,11,14-Eicosatrienoic Acid, Aryl Hydrocarbon Hydroxylases, Cell Cycle Proteins, Cell Division, Cultured Cells, Cyclin-Dependent Kinase Inhibitor p27, Cytochrome P-450 CYP2C9, DNA-Binding Proteins, Dominant Genes, Down-Regulation, Drug Dose-Response Relationship, Enzyme Inhibitors, Forkhead Box Protein O1, Forkhead Transcription Factors, Genetic Promoter Regions, Immunoblotting, Luciferases, Messenger RNA, Northern Blotting, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Physiologic Neovascularization, Plasmids, Small Interfering RNA, Time Factors, Transcription Factors, Transfection, Tumor Suppressor Proteins, Umbilical Veins, Vascular Endothelium, Vasodilator Agents, Western Blotting
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology
Volume:278
Number:32
Page Range:29619-29625
Date:8 August 2003
Official Publication:https://doi.org/10.1074/jbc.M305385200
PubMed:View item in PubMed

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