E2F-1 Regulates Nuclear Factor-κB Activity and Cell Adhesion

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Abstract
Background— The transcription factor E2F-1 promotes vascular smooth muscle cell apoptosis and is reported to inhibit apoptosis induced by tumor necrosis factor (TNF)-α in endothelial cells. Whether E2F-1 overexpression exerts potentially antiinflammatory effects in endothelial cells is not known. Methods and Results— By immunoblotting and immunofluorescence, TNF-α treatment of human aortic endothelial cells (HAECs) with the control vector Ad.null was followed by rapid nuclear translocation of nuclear factor (NF)-κB p65, whereas nuclear translocation of p65 was markedly reduced in HAECs overexpressing E2F-1. Electrophoretic mobility shift assay and gel shift analysis of nuclear cell extracts confirmed that HAECs treated with a recombinant adenovirus encoding E2F-1 failed to associate with the binding domain of p65. Stimulation of the Ad.null-infected endothelial cells with TNF-α resulted in enhanced expression of endothelial intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin and enhanced adhesion of monocytic U937 cells to the HAECs. Adhesion molecule expression and cell adhesion were reduced in E2F-1–transduced HAECs, associated with a marked decrease in phosphorylated IκB-α, required for nuclear translocation of NF-κB p65. Conclusions— These findings suggest that E2F-1 stabilizes IκB and thereby may inhibit NF-κB–dependent processes involved in atherogenesis, including endothelial expression of E-selectin, vascular cellular adhesion molecule-1, and intracellular adhesion molecule-1 and cell adhesion to perturbed endothelial cells.