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on May 8, 2008

Arteriosclerosis, Thrombosis, and Vascular Biology. 2008
Published online before print May 8, 2008, doi: 10.1161/ATVBAHA.108.165811
A more recent version of this article appeared on July 1, 2008
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Submitted on September 11, 2007
Accepted on April 28, 2008

KLF2 Primes the Antioxidant Transcription Factor Nrf2 for Activation in Endothelial Cells

Joost O. Fledderus ; Reinier A. Boon ; Oscar L. Volger ; Hanna Hurttila ; Seppo Ylä-Herttuala ; Hans Pannekoek ; Anna-Liisa Levonen ; and Anton J.G. Horrevoets *

From the Department of Medical Biochemistry (J.O.F., R.A.B., O.L.V., H.P.), Academic Medical Center, University of Amsterdam, The Netherlands; the Department of Biotechnology and Molecular Medicine (H.H., S.Y.-H., A.-L.L.), A.I. Virtanen Institute, University of Kuopio, Finland; and the Department of Molecular Cell Biology and Immunology (O.L.V., A.J.G.H.), VU University Medical Center, Amsterdam, The Netherlands.

* To whom correspondence should be addressed. E-mail: aj.horrevoets{at}vumc.nl.

Objective—Atheroprotective blood flow induces expression of antiinflammatory Krüppel-like factor 2 (KLF2) and activates antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in vascular endothelium. Previously, we obtained KLF2-induced gene expression profiles in ECs, containing several Nrf2 target genes. Our aim was to investigate the role of KLF2 in shear stress–mediated activation of Nrf2 in human umbilical vein endothelial cells (HUVECs).

Methods and Results—Expression of Nrf2 and its targets NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase (HO-1) was elevated by shear and KLF2. KLF2 knockdown showed that shear-induced expression of NQO1 but not Nrf2 was dependent on KLF2. KLF2 overexpression in absence of flow resulted in more efficient activation of Nrf2 by tert-butyl hydroquinone (tBHQ) through enhanced nuclear localization, and promoted expression of a large panel of Nrf2-dependent genes resulting in superior protection against oxidative stress. Comparison of shear-, KLF2-, and Nrf2-induced transcriptomes showed that the majority of shear-modulated gene sets is influenced by KLF2 or Nrf2.

Conclusions—We report that KLF2 substantially enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation. The synergistic activity of these two transcription factors forms a major contribution to the shear stress–elicited transcriptome in endothelial cells.




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