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

doi:10.1161/ATVBAHA.108.165811

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

Nephrology

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1339-46
Number of pages	8
Journal	Arteriosclerosis, Thrombosis and Vascular Biology
Volume	28
Issue number	7
DOIs	https://doi.org/10.1161/ATVBAHA.108.165811
Publication status	Published - Jul 2008

Keywords

Active Transport, Cell Nucleus
Antioxidants
Cells, Cultured
Endothelial Cells
Enzyme Induction
Gene Expression Profiling
Gene Regulatory Networks
Heme Oxygenase-1
Humans
Kruppel-Like Transcription Factors
NAD(P)H Dehydrogenase (Quinone)
NF-E2-Related Factor 2
Oxidants
Oxidative Stress
Pulsatile Flow
RNA Interference
RNA, Small Interfering
Stress, Mechanical
Transfection
Up-Regulation
tert-Butylhydroperoxide

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10.1161/ATVBAHA.108.165811

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@article{12d35f73eeb84ba9a2f726d4c9602441,

title = "KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells",

abstract = "OBJECTIVE: Atheroprotective blood flow induces expression of anti-inflammatory Kr{\"u}ppel-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.",

keywords = "Active Transport, Cell Nucleus, Antioxidants, Cells, Cultured, Endothelial Cells, Enzyme Induction, Gene Expression Profiling, Gene Regulatory Networks, Heme Oxygenase-1, Humans, Kruppel-Like Transcription Factors, NAD(P)H Dehydrogenase (Quinone), NF-E2-Related Factor 2, Oxidants, Oxidative Stress, Pulsatile Flow, RNA Interference, RNA, Small Interfering, Stress, Mechanical, Transfection, Up-Regulation, tert-Butylhydroperoxide",

author = "Fledderus, \{Joost O\} and Boon, \{Reinier A\} and Volger, \{Oscar L\} and Hanna Hurttila and Seppo Yl{\"a}-Herttuala and Hans Pannekoek and Anna-Liisa Levonen and Horrevoets, \{Anton J G\}",

year = "2008",

month = jul,

doi = "10.1161/ATVBAHA.108.165811",

language = "English",

volume = "28",

pages = "1339--46",

journal = "Arteriosclerosis, Thrombosis and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams \& Wilkins",

number = "7",

}

TY - JOUR

T1 - KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells

AU - Fledderus, Joost O

AU - Boon, Reinier A

AU - Volger, Oscar L

AU - Hurttila, Hanna

AU - Ylä-Herttuala, Seppo

AU - Pannekoek, Hans

AU - Levonen, Anna-Liisa

AU - Horrevoets, Anton J G

PY - 2008/7

Y1 - 2008/7

N2 - 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.

AB - 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.

KW - Active Transport, Cell Nucleus

KW - Antioxidants

KW - Cells, Cultured

KW - Endothelial Cells

KW - Enzyme Induction

KW - Gene Expression Profiling

KW - Gene Regulatory Networks

KW - Heme Oxygenase-1

KW - Humans

KW - Kruppel-Like Transcription Factors

KW - NAD(P)H Dehydrogenase (Quinone)

KW - NF-E2-Related Factor 2

KW - Oxidants

KW - Oxidative Stress

KW - Pulsatile Flow

KW - RNA Interference

KW - RNA, Small Interfering

KW - Stress, Mechanical

KW - Transfection

KW - Up-Regulation

KW - tert-Butylhydroperoxide

U2 - 10.1161/ATVBAHA.108.165811

DO - 10.1161/ATVBAHA.108.165811

M3 - Article

C2 - 18467642

SN - 1079-5642

VL - 28

SP - 1339

EP - 1346

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

IS - 7

ER -

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

Abstract

Keywords

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