title: Piceatannol attenuates homocysteine-induced endoplasmic reticulum stress and endothelial cell damage via heme oxygenase-1 expression.
abstract: A growing body of evidence implicates endoplasmic reticulum (ER)-induced cellular dysfunction and apoptosis as important factors to a variety of diseases. In endothelial cells (ECs), the sulfur-containing amino acid homocysteine (Hcy) causes EC apoptosis and reactive oxygen species (ROS) generation through induction of ER stress. Here, we have investigated whether piceatannol (Pic), a resveratrol analog, could protect ECs against Hcy-induced apoptosis, oxidative stress and ER stress, with specific emphasis on heme oxygenase-1 (HO-1). In human ECs, we determined the effects of Hcy and Pic on annexin V positivity, glucose-regulated protein 78 kDa (GRP78) and C/EBP homologous protein (CHOP) expression, X-box binding protein 1 (Xbp-1) mRNA slicing, and ROS-sensitive dihydroethidium (DHE) oxidation. Hcy increased annexin V-positive cells, DHE oxidation, GRP78 and CHOP expression and Xbp-1 mRNA splicing, indicating that Hcy induces apoptosis, oxidative stress and ER stress. Pretreatment of ECs with Pic significantly inhibited Hcy-induced apoptosis, ROS generation and ER stress. Pic also increased HO-1 expression via activation of nuclear factor-E2-related factor 2 (Nrf2). Interestingly, the inhibitory effects of Pic on Hcy-induced apoptosis, ROS generation and ER stress were abolished by down-regulation of HO-1 expression, while mimicked by treatment of ECs with the HO-1 inducer hemin. Overall, these results suggest that Pic may protect ECs against Hcy-induced apoptosis, oxidative stress and ER stress via Nrf2-dependent HO-1 expression.
authors.affiliation: Department of Neurosurgery, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea.
authors.forename: Jin-Sang
authors.initials: JS
authors.lastname: Kil
authors.affiliation: Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea.
authors.forename: Sun-Oh
authors.initials: SO
authors.lastname: Jeong
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea. hopae@wku.ac.kr.
authors.forename: Hyun-Ock
authors.initials: HO
authors.lastname: Pae
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D013267:Stilbenes; D006710:Homocysteine; C041525:3,3',4,5'-tetrahydroxystilbene; D051547:Heme Oxygenase-1
keywords: Apoptosis; Endoplasmic reticulum stress; Endothelial cell; Heme oxygenase-1; Homocysteine; Piceatannol