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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1339.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

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; 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.

Correspondence to Dr Anton J.G. Horrevoets, Department of Molecular Cell Biology and Immunology, Room B244, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail aj.horrevoets{at}vumc.nl

Abstract

Objective— Atheroprotective blood flow induces expression of anti-inflammatory 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.

The role of KLF2 in shear-induced Nrf2-dependent gene expression in HUVECs was studied. Nrf2-mediated antioxidant transcription was increased by KLF2 through enhanced Nrf2 nuclear localization and activation which resulted in an enhanced protection against oxidative stress. We report that KLF2 and Nrf2 give a major contribution to the antioxidant and antiinflammatory endothelial response to flow.

Key Words: endothelium • shear stress • KLF2 • oxidative stress • Nrf2