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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 28; no. 7; pp. 1339 - 1346
• Main Authors: Fledderus, Joost O, Boon, Reinier A, Volger, Oscar L, Hurttila, Hanna, Ylä-Herttuala, Seppo, Pannekoek, Hans, Levonen, Anna-Liisa, Horrevoets, Anton J.G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.07.2008; Hagerstown, MD Lippincott
• Subjects: Active Transport, Cell Nucleus; Antioxidants - metabolism; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial Cells - metabolism; Enzyme Induction; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Regulatory Networks; Heme Oxygenase-1 - biosynthesis; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Medical sciences; NAD(P)H Dehydrogenase (Quinone) - biosynthesis; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidants - pharmacology; Oxidative Stress; Pulsatile Flow; RNA Interference; RNA, Small Interfering - metabolism; Stress, Mechanical; tert-Butylhydroperoxide - pharmacology; Transfection; Up-Regulation; Vertebrates: cardiovascular system; Vascular disease; Oxidative stress; Endothelial cell; Nrf2; Atherosclerosis; Shear stress; Cardiovascular disease; Antioxidant; Transcription factor; KLF2; Endothelium
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.108.165811

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.