11,12-epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating p27Kip1

被引:143
作者
Potente, M [1 ]
Fisslthaler, B [1 ]
Busse, R [1 ]
Fleming, I [1 ]
机构
[1] Univ Frankfurt Klinikum, Inst Kardiovask Physiol, D-60590 Frankfurt, Germany
关键词
D O I
10.1074/jbc.M305385200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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).
引用
收藏
页码:29619 / 29625
页数:7
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