Objective: High levels of homocysteine (Hcy) induce a sustained injury on arterial endothelial cells, which accelerates the development of thrombosis and atherosclerosis. Hcy specifically inhibits the growth of endothelial cells. The present study investigated the signaling pathways underlying this cell-cycle effect. Methods: Human umbilical venous endothelial cells were treated with Hcy, and/or LY294002, okadaic acid, peroxovanadate (PV), antisense Akt, phosphorylation of Akt and FKHRL1 proteins. p27kip1 protein levels were measured with Western blotting, and Akt kinase activity and cell cycle were measured with immunoprecipitation and flow cytometry, respectively. Results: We demonstrate that Hcy induces dephosphorylation of Akt and FKHRL1 and upregulates the cyclin-dependent kinase inhibitors p27kip1 in a time- and dose-dependent manner. Phosphatidylinositol-3 kinase (PI3K) activator PV and phosphatase 2A inhibitor okadaic acid could reverse it, which suggests it was dependent on PI3K activity. Moreover, Hcy induces cell cycle G1 phase arrest prevented by pretreatment with PV and okadaic acid. Transfection with specific antisense oligonucleotides to Akt further proves the observations. Conclusions: The studies implied that a novel signaling pathway, PI3K/Akt/FOXO, might play an important role in mediating cell cycle G1 arrest in endothelial cells.

Keywords:
Homocysteine, Cell cycle arrest, Akt, FKHRL1, p27kip1
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© 2005 S. Karger AG, Basel
2005
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