KLF2 suppresses TGF-β signaling in endothelium through induction of Smad7 and inhibition of AP-1

Reinier A. Boon, Joost O. Fledderus, Oscar L. Volger, Eva J.A. Van Wanrooij, Evangelia Pardali, Frank Weesie, Johan Kuiper, Hans Pannekoek, Peter Ten Dijke, Anton J.G. Horrevoets*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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-β (TGF-β) 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-β-inducible genes. Both baseline and TGF-β-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-β-induced Smad4-mediated transcriptional activity. This is achieved through TGF-β-independent induction of inhibitory Smad7. Additionally, a full inhibition of TGF-β signaling is functionally achieved through a simultaneous suppression of activator protein 1 (AP-1), which is an essential cofactor for TGF-β-dependent transcription of many genes. CONCLUSIONS - The concerted mechanism by which KLF2 inhibits TGF-β 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.

Original languageEnglish
Pages (from-to)532-539
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number3
Publication statusPublished - 1 Mar 2007

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