on December 28, 2006
Published online before print December 28, 2006, doi: 10.1161/01.ATV.0000256466.65450.ce
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 21, 2006
Accepted on December 7, 2006
KLF2 Suppresses TGF-
Signaling in Endothelium Through Induction of Smad7 and Inhibition of AP-1
Reinier A. Boon ;
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.
* To whom correspondence should be addressed. 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-
(TGF-) 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--inducible genes. Both baseline and TGF--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--induced Smad4-mediated transcriptional activity. This is achieved through TGF--independent induction of inhibitory Smad7. Additionally, a full inhibition of TGF- signaling is functionally achieved through a simultaneous suppression of activator protein 1 (AP-1), which is an essential cofactor for TGF--dependent transcription of many genes.
Conclusions--The concerted mechanism by which KLF2 inhibits TGF- 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.
Key words: blood flow • endothelium • gene expression • growth factors • vascular biology
This article has been cited by other articles:
 |
|
 |
|
  E. S. Shao, L. Lin, Y. Yao, and K. I. Bostrom Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells Blood, September 3, 2009; 114(10): 2197 - 2206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rohlena, O. L. Volger, J. D. van Buul, L. H.P. Hekking, J. M. van Gils, P. I. Bonta, R. D. Fontijn, J. A. Post, P. L. Hordijk, and A. J.G. Horrevoets Endothelial CD81 is a marker of early human atherosclerotic plaques and facilitates monocyte adhesion Cardiovasc Res, January 1, 2009; 81(1): 187 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. O. Fledderus, R. A. Boon, O. L. Volger, H. Hurttila, S. Yla-Herttuala, H. Pannekoek, A.-L. Levonen, and A. J.G. Horrevoets KLF2 Primes the Antioxidant Transcription Factor Nrf2 for Activation in Endothelial Cells Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1339 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. W. Groenendijk, K. Van der Heiden, B. P. Hierck, and R. E. Poelmann The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model Physiology, December 1, 2007; 22(6): 380 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. B. Atkins and M. K. Jain Role of Kruppel-Like Transcription Factors in Endothelial Biology Circ. Res., June 22, 2007; 100(12): 1686 - 1695. [Abstract] [Full Text] [PDF]
|
|