title: Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells.
abstract: 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.
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan ; Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan ; Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan.
authors.forename: Tsung-Hsuan
authors.initials: TH
authors.lastname: Lai
authors.affiliation: Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan ; Department of Recreation and Healthcare Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Jiunn-Min
authors.initials: JM
authors.lastname: Shieh
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Tsou
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Wu
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006046:Gold / Q000737:chemistry*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000199:Actins; D000975:Antioxidants; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D006046:Gold; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Keap1; endothelium; inflammation; nuclear export; translocation; tyrosine phosphorylation