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  • Title: KLF2 suppresses TGF-beta signaling in endothelium through induction of Smad7 and inhibition of AP-1.
    Author: Boon RA, Fledderus JO, Volger OL, van Wanrooij EJ, Pardali E, Weesie F, Kuiper J, Pannekoek H, ten Dijke P, Horrevoets AJ.
    Journal: Arterioscler Thromb Vasc Biol; 2007 Mar; 27(3):532-9. PubMed ID: 17194892.
    Abstract:
    OBJECTIVE: The flow-responsive Kruppel-like factor 2 (KLF2) is crucial for maintaining endothelial cell quiescence. Here, we describe its detailed effects on transforming growth factor-beta (TGF-beta) signaling, which normally has proatherogenic effects on endothelium. METHODS AND RESULTS: In-depth analysis of genome-wide expression data shows that prolonged lentiviral-mediated overexpression of KLF2 in human umbilical vein endothelial cells (HUVECs) diminishes the expression of a large panel of established TGF-beta-inducible genes. Both baseline and TGF-beta-induced expression levels of plasminogen activator inhibitor 1 (PAI-1) and thrombospondin-1 are greatly diminished by KLF2. Using a combination of ectopic expression, small interfering RNA-mediated knockdown, and promoter activity assays, we show that KLF2 partly inhibits the phosphorylation and subsequent nuclear accumulation of Smad2, thereby suppressing the TGF-beta-induced Smad4-mediated transcriptional activity. This is achieved through TGF-beta-independent induction of inhibitory Smad7. Additionally, a full inhibition of TGF-beta signaling is functionally achieved through a simultaneous suppression of activator protein 1 (AP-1), which is an essential cofactor for TGF-beta-dependent transcription of many genes. CONCLUSIONS: The concerted mechanism by which KLF2 inhibits TGF-beta signaling through induction of inhibitory Smad7 and attenuation of AP-1 activity provides a novel mechanism by which KLF2 contributes to sustaining a quiescent, atheroprotective status of vascular endothelium.
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