KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells

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

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159 Citations (Scopus)

Abstract

Objective-Atheroprotective blood flow induces expression of anti-inflammatory Kruppel-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
Original languageEnglish
Pages (from-to)1339-1346
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number7
DOIs
Publication statusPublished - 2008

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