Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

Chung-Yu Hsieh; Huai-Yu Hsiao; Wan-Yi Wu; Ching-Ann Liu; Yu-Chih Tsai; Yuen-Jen Chao; Danny-Ling Wang; Hsyue-Jen Hsieh

doi:10.1186/1423-0127-16-12

Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

Chung-Yu Hsieh, Huai-Yu Hsiao, Wan-Yi Wu, Ching-Ann Liu, Yu-Chih Tsai, Yuen-Jen Chao, Danny-Ling Wang, Hsyue-Jen Hsieh

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

61 Citations (Scopus)

Abstract

Background. Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress. Results. Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1. Conclusion. Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.

Original language	English
Journal	Journal of Biomedical Science
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/1423-0127-16-12
Publication status	Published - 2009
Externally published	Yes

Keywords

heme oxygenase 1
phosphatidylinositol 3 kinase
protein kinase C inhibitor
reactive oxygen metabolite
transcription factor Nrf2
enzyme inhibitor
hydrogen peroxide
nitric oxide synthase
oxidizing agent
article
controlled study
endothelium cell
gene control
genetic transcription
human
human cell
nucleotide sequence
priority journal
protein expression
active transport
cell culture
cell nucleus
cytology
drug antagonism
gene expression regulation
genetics
mechanical stress
metabolism
physiology
shear strength
1-Phosphatidylinositol 3-Kinase
Active Transport, Cell Nucleus
Cell Nucleus
Cells, Cultured
Endothelial Cells
Enzyme Inhibitors
Gene Expression Regulation
Heme Oxygenase-1
Humans
Hydrogen Peroxide
NF-E2-Related Factor 2
Nitric Oxide Synthase
Oxidants
Reactive Oxygen Species
Shear Strength
Stress, Mechanical

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10.1186/1423-0127-16-12

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Cite this

@article{6e9e79a59505495188c39d0f57da2ebc,

title = "Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells",

abstract = "Background. Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress. Results. Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1. Conclusion. Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.",

keywords = "heme oxygenase 1, phosphatidylinositol 3 kinase, protein kinase C inhibitor, reactive oxygen metabolite, transcription factor Nrf2, enzyme inhibitor, hydrogen peroxide, nitric oxide synthase, oxidizing agent, article, controlled study, endothelium cell, gene control, genetic transcription, human, human cell, nucleotide sequence, priority journal, protein expression, active transport, cell culture, cell nucleus, cytology, drug antagonism, gene expression regulation, genetics, mechanical stress, metabolism, physiology, shear strength, 1-Phosphatidylinositol 3-Kinase, Active Transport, Cell Nucleus, Cell Nucleus, Cells, Cultured, Endothelial Cells, Enzyme Inhibitors, Gene Expression Regulation, Heme Oxygenase-1, Humans, Hydrogen Peroxide, NF-E2-Related Factor 2, Nitric Oxide Synthase, Oxidants, Reactive Oxygen Species, Shear Strength, Stress, Mechanical",

author = "Chung-Yu Hsieh and Huai-Yu Hsiao and Wan-Yi Wu and Ching-Ann Liu and Yu-Chih Tsai and Yuen-Jen Chao and Danny-Ling Wang and Hsyue-Jen Hsieh",

note = "被引用次數：24 Export Date: 28 March 2016 CODEN: JBCIE 通訊地址: Hsieh, H.-J.; Department of Chemical Engineering, National Taiwan University, Taipei 106, Taiwan; 電子郵件： [email protected] 分析序列編號: GENBANK: BC011558; 化學物質/CAS: phosphatidylinositol 3 kinase, 115926-52-8; hydrogen peroxide, 7722-84-1; nitric oxide synthase, 125978-95-2; 1-Phosphatidylinositol 3-Kinase, 2.7.1.137; Enzyme Inhibitors; Heme Oxygenase-1, 1.14.99.3; Hydrogen Peroxide, 7722-84-1; NF-E2-Related Factor 2; Nitric Oxide Synthase, 1.14.13.39; Oxidants; Reactive Oxygen Species 參考文獻: Traub, O., Berk, B.C., Laminar shear stress: Mechanisms by which endothelial cells transduce an atheroprotective force (1998) Arterioscler Thromb Vasc Biol, 18, pp. 677-685. , 9598824; Brooks, A.R., Lelkes, P.I., Rubanyi, G.M., Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow (2002) Physiol Genomics, 9, pp. 27-41. , 11948288; Chen, B.P., Li, Y.S., Zhao, Y., Chen, K.D., Li, S., Lao, J., Yuan, S., Chien, S., DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress (2001) Physiol Genomics, 7, pp. 55-63. , 10.1006/geno.2001.6511 11595792; McCormick, S.M., Eskin, S.G., McIntire, L.V., Teng, C.L., Lu, C.M., Russell, C.G., Chittur, K.K., DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells (2001) Proc Natl Acad Sci USA, 98, pp. 8955-8960. , 11481467 10.1073/pnas.171259298; McCormick, S.M., Frye, S.R., Eskin, S.G., Teng, C.L., Lu, C.M., Russell, C.G., Chittur, K.K., McIntire, L.V., Microarray analysis of shear stressed endothelial cells (2003) Biorheology, 40, pp. 5-11. , 12454381; Chen, X.L., Varner, S.E., Rao, A.S., Grey, J.Y., Thomas, S., Cook, C.K., Wasserman, M.A., Kunsch, C., Laminar flow induction of antioxidant response element-mediated genes in endothelial cells: A novel anti-inflammatory mechanism (2003) J Biol Chem, 278, pp. 703-711. , 10.1074/jbc.M203161200 12370194; Dimmeler, S., Assmus, B., Hermann, C., Haendeler, J., Zeiher, A.M., Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: Involvement in suppression of apoptosis (1998) Circ Res, 83, pp. 334-341. , 9710127; Tedgui, A., Mallat, Z., Anti-inflammatory mechanisms in the vascular wall (2001) Circ Res, 88, pp. 877-887. , 10.1161/hh0901.090440 11348996; Akimoto, S., Mitsumata, M., Sasaguri, T., Yoshida, Y., Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) (2000) Circ Res, 86, pp. 185-190. , 10666414; Lin, K., Hsu, P.P., Chen, B.P., Yuan, S., Usami, S., Shyy, J.Y., Li, Y.S., Chien, S., Molecular mechanism of endothelial growth arrest by laminar shear stress (2000) Proc Natl Acad Sci USA, 97, pp. 9385-9389. , 10920209 10.1073/pnas.170282597; Hojo, Y., Saito, Y., Tanimoto, T., Hoefen, R.J., Baines, C.P., Yamamoto, K., Haendeler, J., Berk, B.C., Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism (2002) Circ Res, 91, pp. 712-718. , 10.1161/01.RES.0000037981.97541.25 12386148; Ni, C.W., Hsieh, H.J., Chao, Y.J., Wang, D.L., Shear Flow Attenuates Serum-induced STAT3 Activation in Endothelial Cells (2003) J Biol Chem, 278, pp. 19702-19708. , 10.1074/jbc.M300893200 12637510; Ni, C.W., Hsieh, H.J., Chao, Y.J., Wang, D.L., Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow (2004) Am J Physiol Cell Physiol, 287, pp. 771-C780. , 10.1152/ajpcell.00532.2003 15151905; Surapisitchat, J., Hoefen, R.J., Pi, X., Yoshizumi, M., Yan, C., Berk, B.C., Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members (2001) Proc Natl Acad Sci USA, 98, pp. 6476-6481. , 11353829 10.1073/pnas.101134098; Go, Y.M., Park, H., Maland, M.C., Darley-Usmar, V.M., Stoyanov, B., Wetzker, R., Jo, H., Phosphatidylinositol 3-kinase gamma mediates shear stress-dependent activation of JNK in endothelial cells (1998) Am J Physiol, 275, pp. 1898-H1904. , 9815099; Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., Zeiher, A.M., Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation (1999) Nature, 399, pp. 601-605. , 10.1038/21224 10376603; Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Sessa, W.C., Regulation of endothelium-derived nitric oxide production by the protein kinase Akt (1999) Nature, 399, pp. 597-601. , 10.1038/21218 10376602; Chiu, J.J., Wung, B.S., Hsieh, H.J., Lo, L.W., Wang, D.L., Nitric oxide regulates shear stress-induced early growth response-1. 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year = "2009",

doi = "10.1186/1423-0127-16-12",

language = "English",

volume = "16",

journal = "Journal of Biomedical Science",

issn = "1021-7770",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

AU - Hsieh, Chung-Yu

AU - Hsiao, Huai-Yu

AU - Wu, Wan-Yi

AU - Liu, Ching-Ann

AU - Tsai, Yu-Chih

AU - Chao, Yuen-Jen

AU - Wang, Danny-Ling

AU - Hsieh, Hsyue-Jen

N1 - 被引用次數：24 Export Date: 28 March 2016 CODEN: JBCIE 通訊地址: Hsieh, H.-J.; Department of Chemical Engineering, National Taiwan University, Taipei 106, Taiwan; 電子郵件： [email protected] 分析序列編號: GENBANK: BC011558; 化學物質/CAS: phosphatidylinositol 3 kinase, 115926-52-8; hydrogen peroxide, 7722-84-1; nitric oxide synthase, 125978-95-2; 1-Phosphatidylinositol 3-Kinase, 2.7.1.137; Enzyme Inhibitors; Heme Oxygenase-1, 1.14.99.3; Hydrogen Peroxide, 7722-84-1; NF-E2-Related Factor 2; Nitric Oxide Synthase, 1.14.13.39; Oxidants; Reactive Oxygen Species 參考文獻: Traub, O., Berk, B.C., Laminar shear stress: Mechanisms by which endothelial cells transduce an atheroprotective force (1998) Arterioscler Thromb Vasc Biol, 18, pp. 677-685. , 9598824; Brooks, A.R., Lelkes, P.I., Rubanyi, G.M., Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow (2002) Physiol Genomics, 9, pp. 27-41. , 11948288; Chen, B.P., Li, Y.S., Zhao, Y., Chen, K.D., Li, S., Lao, J., Yuan, S., Chien, S., DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress (2001) Physiol Genomics, 7, pp. 55-63. , 10.1006/geno.2001.6511 11595792; McCormick, S.M., Eskin, S.G., McIntire, L.V., Teng, C.L., Lu, C.M., Russell, C.G., Chittur, K.K., DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells (2001) Proc Natl Acad Sci USA, 98, pp. 8955-8960. , 11481467 10.1073/pnas.171259298; McCormick, S.M., Frye, S.R., Eskin, S.G., Teng, C.L., Lu, C.M., Russell, C.G., Chittur, K.K., McIntire, L.V., Microarray analysis of shear stressed endothelial cells (2003) Biorheology, 40, pp. 5-11. , 12454381; Chen, X.L., Varner, S.E., Rao, A.S., Grey, J.Y., Thomas, S., Cook, C.K., Wasserman, M.A., Kunsch, C., Laminar flow induction of antioxidant response element-mediated genes in endothelial cells: A novel anti-inflammatory mechanism (2003) J Biol Chem, 278, pp. 703-711. , 10.1074/jbc.M203161200 12370194; Dimmeler, S., Assmus, B., Hermann, C., Haendeler, J., Zeiher, A.M., Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: Involvement in suppression of apoptosis (1998) Circ Res, 83, pp. 334-341. , 9710127; Tedgui, A., Mallat, Z., Anti-inflammatory mechanisms in the vascular wall (2001) Circ Res, 88, pp. 877-887. , 10.1161/hh0901.090440 11348996; Akimoto, S., Mitsumata, M., Sasaguri, T., Yoshida, Y., Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) (2000) Circ Res, 86, pp. 185-190. , 10666414; Lin, K., Hsu, P.P., Chen, B.P., Yuan, S., Usami, S., Shyy, J.Y., Li, Y.S., Chien, S., Molecular mechanism of endothelial growth arrest by laminar shear stress (2000) Proc Natl Acad Sci USA, 97, pp. 9385-9389. , 10920209 10.1073/pnas.170282597; Hojo, Y., Saito, Y., Tanimoto, T., Hoefen, R.J., Baines, C.P., Yamamoto, K., Haendeler, J., Berk, B.C., Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism (2002) Circ Res, 91, pp. 712-718. , 10.1161/01.RES.0000037981.97541.25 12386148; Ni, C.W., Hsieh, H.J., Chao, Y.J., Wang, D.L., Shear Flow Attenuates Serum-induced STAT3 Activation in Endothelial Cells (2003) J Biol Chem, 278, pp. 19702-19708. , 10.1074/jbc.M300893200 12637510; Ni, C.W., Hsieh, H.J., Chao, Y.J., Wang, D.L., Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow (2004) Am J Physiol Cell Physiol, 287, pp. 771-C780. , 10.1152/ajpcell.00532.2003 15151905; Surapisitchat, J., Hoefen, R.J., Pi, X., Yoshizumi, M., Yan, C., Berk, B.C., Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members (2001) Proc Natl Acad Sci USA, 98, pp. 6476-6481. , 11353829 10.1073/pnas.101134098; Go, Y.M., Park, H., Maland, M.C., Darley-Usmar, V.M., Stoyanov, B., Wetzker, R., Jo, H., Phosphatidylinositol 3-kinase gamma mediates shear stress-dependent activation of JNK in endothelial cells (1998) Am J Physiol, 275, pp. 1898-H1904. , 9815099; Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., Zeiher, A.M., Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation (1999) Nature, 399, pp. 601-605. , 10.1038/21224 10376603; Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Sessa, W.C., Regulation of endothelium-derived nitric oxide production by the protein kinase Akt (1999) Nature, 399, pp. 597-601. , 10.1038/21218 10376602; Chiu, J.J., Wung, B.S., Hsieh, H.J., Lo, L.W., Wang, D.L., Nitric oxide regulates shear stress-induced early growth response-1. 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PY - 2009

Y1 - 2009

N2 - Background. Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress. Results. Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1. Conclusion. Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.

AB - Background. Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress. Results. Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1. Conclusion. Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.

KW - heme oxygenase 1

KW - phosphatidylinositol 3 kinase

KW - protein kinase C inhibitor

KW - reactive oxygen metabolite

KW - transcription factor Nrf2

KW - enzyme inhibitor

KW - hydrogen peroxide

KW - nitric oxide synthase

KW - oxidizing agent

KW - article

KW - controlled study

KW - endothelium cell

KW - gene control

KW - genetic transcription

KW - human

KW - human cell

KW - nucleotide sequence

KW - priority journal

KW - protein expression

KW - active transport

KW - cell culture

KW - cell nucleus

KW - cytology

KW - drug antagonism

KW - gene expression regulation

KW - genetics

KW - mechanical stress

KW - metabolism

KW - physiology

KW - shear strength

KW - 1-Phosphatidylinositol 3-Kinase

KW - Active Transport, Cell Nucleus

KW - Cell Nucleus

KW - Cells, Cultured

KW - Endothelial Cells

KW - Enzyme Inhibitors

KW - Gene Expression Regulation

KW - Heme Oxygenase-1

KW - Humans

KW - Hydrogen Peroxide

KW - NF-E2-Related Factor 2

KW - Nitric Oxide Synthase

KW - Oxidants

KW - Reactive Oxygen Species

KW - Shear Strength

KW - Stress, Mechanical

U2 - 10.1186/1423-0127-16-12

DO - 10.1186/1423-0127-16-12

M3 - Article

SN - 1021-7770

VL - 16

JO - Journal of Biomedical Science

JF - Journal of Biomedical Science

IS - 1

ER -

Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

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