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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:532.)
© 2007 American Heart Association, Inc.

Vascular Biology

KLF2 Suppresses TGF-ß 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

From the Department of Medical Biochemistry (R.A.B., J.O.F., O.L.V., F.W., H.P., A.J.G.H.), Academic Medical Center, University of Amsterdam; the Department of Molecular Cell Biology (E.P., P.t.D.), Leids Universitair Medisch Centrum, Leiden University; and the Division of Biopharmaceutics (E.J.A.v.W., J.K.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.

Correspondence to Anton J.G. Horrevoets, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands. E-mail A.J.Horrevoets{at}amc.uva.nl

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

Conclusions— The concerted mechanism by which KLF2 inhibits TGF-ß 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.

TGF-ß signaling in endothelium is generally considered proatherogenic. The shear stress–induced transcription factor KLF2 inhibits endothelial TGF-ß signaling by inducing the inhibitory Smad7 and suppressing the cofactor AP-1. This mechanism may contribute to the KLF2-mediated atheroprotection of shear stress.

Key Words: blood flow • endothelium • gene expression • growth factors • vascular biology

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