Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells

Tsung-Hsuan Lai,1–3 Jiunn-Min Shieh,4,5 Chih-Jen Tsou,1 Wen-Bin Wu11School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 2Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan; 3Institute of Systems Biology and Bioinformatics, National Central...

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Main Authors: Lai TH, Shieh JM, Tsou CJ, Wu WB
Format: Article
Language:English
Published: Dove Medical Press 2015-09-01
Series:International Journal of Nanomedicine
Online Access:https://www.dovepress.com/gold-nanoparticles-induce-heme-oxygenase-1-expression-through-nrf2-act-peer-reviewed-article-IJN
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spelling doaj-466ed07aefb845ac8f1f1cb55a9cf0f52020-11-25T00:13:19ZengDove Medical PressInternational Journal of Nanomedicine1178-20132015-09-012015default5925593923766Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cellsLai THShieh JMTsou CJWu WBTsung-Hsuan Lai,1–3 Jiunn-Min Shieh,4,5 Chih-Jen Tsou,1 Wen-Bin Wu11School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 2Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan; 3Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan; 4Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan; 5Department of Recreation and Healthcare Management, Chia Nan University of Pharmacy and Science, Tainan, TaiwanAbstract: It has been reported that increased levels and activity of the heme oxygenase-1 (HO-1) protein ameliorate tissue injuries. In the present study, we investigated the effects and mechanisms of action of gold nanoparticles (AuNPs) on HO-1 protein expression in human vascular endothelial cells (ECs). The AuNPs induced HO-1 protein and mRNA expression in a concentration- and time-dependent manner. The induction was reduced by the thiol-containing antioxidants, including N-acetylcysteine and glutathione, but not by the non-thiol-containing antioxidants and inhibitors that block the enzymes for intracellular reactive oxygen species generation. The AuNPs enhanced Nrf2 protein levels but did not affect Nrf2 mRNA expression. In response to the AuNP treatment, the cytosolic Nrf2 translocated to the nucleus, and, concomitantly, Bach1 exited the nucleus and its tyrosine phosphorylation increased. The chromatin immunoprecipitation assay revealed that the translocated Nrf2 bound to the antioxidant-response element located in the E2 enhancer region of the HO-1 gene promoter and acted as a transcription factor. Although N-acetylcysteine inhibited the AuNP-induced Nrf2 nuclear translocation, the AuNPs did not promote intracellular reactive oxygen species production or endoplasmic reticulum stress in the ECs. Knockdown of Nrf2 expression by RNA interference significantly inhibited AuNP-induced HO-1 expression at the protein and mRNA levels. In summary, AuNPs enhance the levels and nuclear translocation of the Nrf2 protein and Bach1 export/tyrosine phosphorylation, leading to Nrf2 binding to the HO-1 E2 enhancer promoter region to drive HO-1 expression in ECs. This study, together with our parallel findings, demonstrates that AuNPs can act as an HO-1 inducer, which may partially contribute to their anti-inflammatory bioactivity in human vascular ECs.Keywords: endothelium, inflammation, Keap1, nuclear export, translocation, tyrosine phosphorylationhttps://www.dovepress.com/gold-nanoparticles-induce-heme-oxygenase-1-expression-through-nrf2-act-peer-reviewed-article-IJN
collection DOAJ
language English
format Article
sources DOAJ
author Lai TH
Shieh JM
Tsou CJ
Wu WB
spellingShingle Lai TH
Shieh JM
Tsou CJ
Wu WB
Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells
International Journal of Nanomedicine
author_facet Lai TH
Shieh JM
Tsou CJ
Wu WB
author_sort Lai TH
title Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells
title_short Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells
title_full Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells
title_fullStr Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells
title_full_unstemmed Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells
title_sort gold nanoparticles induce heme oxygenase-1 expression through nrf2 activation and bach1 export in human vascular endothelial cells
publisher Dove Medical Press
series International Journal of Nanomedicine
issn 1178-2013
publishDate 2015-09-01
description Tsung-Hsuan Lai,1–3 Jiunn-Min Shieh,4,5 Chih-Jen Tsou,1 Wen-Bin Wu11School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 2Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan; 3Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan; 4Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan; 5Department of Recreation and Healthcare Management, Chia Nan University of Pharmacy and Science, Tainan, TaiwanAbstract: It has been reported that increased levels and activity of the heme oxygenase-1 (HO-1) protein ameliorate tissue injuries. In the present study, we investigated the effects and mechanisms of action of gold nanoparticles (AuNPs) on HO-1 protein expression in human vascular endothelial cells (ECs). The AuNPs induced HO-1 protein and mRNA expression in a concentration- and time-dependent manner. The induction was reduced by the thiol-containing antioxidants, including N-acetylcysteine and glutathione, but not by the non-thiol-containing antioxidants and inhibitors that block the enzymes for intracellular reactive oxygen species generation. The AuNPs enhanced Nrf2 protein levels but did not affect Nrf2 mRNA expression. In response to the AuNP treatment, the cytosolic Nrf2 translocated to the nucleus, and, concomitantly, Bach1 exited the nucleus and its tyrosine phosphorylation increased. The chromatin immunoprecipitation assay revealed that the translocated Nrf2 bound to the antioxidant-response element located in the E2 enhancer region of the HO-1 gene promoter and acted as a transcription factor. Although N-acetylcysteine inhibited the AuNP-induced Nrf2 nuclear translocation, the AuNPs did not promote intracellular reactive oxygen species production or endoplasmic reticulum stress in the ECs. Knockdown of Nrf2 expression by RNA interference significantly inhibited AuNP-induced HO-1 expression at the protein and mRNA levels. In summary, AuNPs enhance the levels and nuclear translocation of the Nrf2 protein and Bach1 export/tyrosine phosphorylation, leading to Nrf2 binding to the HO-1 E2 enhancer promoter region to drive HO-1 expression in ECs. This study, together with our parallel findings, demonstrates that AuNPs can act as an HO-1 inducer, which may partially contribute to their anti-inflammatory bioactivity in human vascular ECs.Keywords: endothelium, inflammation, Keap1, nuclear export, translocation, tyrosine phosphorylation
url https://www.dovepress.com/gold-nanoparticles-induce-heme-oxygenase-1-expression-through-nrf2-act-peer-reviewed-article-IJN
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