title: Fatty acid epoxyisoprostane E2 stimulates an oxidative stress response in endothelial cells.
abstract: Atherosclerosis is the main underlying cause of major cardiovascular diseases such as stroke and heart attack. Oxidized phospholipids such as oxidized 1-palmitoyl-2-arachidonoyl-sn-Glycero-3-phosphorylcholine (OxPAPC) accumulate in lesions of and promote atherosclerosis. OxPAPC activates endothelial cells, a critical early event of atherogenesis. Epoxyisoprostane E2 (EI) is an oxidized fatty acid contained at the sn-2 position of 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine (PEIPC), the most active component of OxPAPC in regulating inflammation. OxPAPC and its components including PEIPC activate endothelial cells to express an array of genes in different categories including oxidative stress response genes such as tumor suppressor gene OKL38 and Heme oxygenase-1 (HO-1). EI can be released by lipase from PEIPC. In this study, we examined the ability of EI to stimulate oxidative stress response in endothelial cells. EI released from OxPAPC and synthetic EI stimulated the expression of oxidative stress response gene OKL38 and antioxidant gene HO-1. Treatment of endothelial cells with EI increased the production of superoxide. NADPH oxidase inhibitor Apocynin and superoxide scavenger N-acetyl-cysteine (NAC) significantly attenuated EI-stimulated expression of OKL38 and HO-1. We further demonstrated that EI activated oxidative stress-sensitive transcription factor Nrf2. Silencing of Nrf2 with siRNA significantly reduced EI stimulated expression of OKL38 and HO-1. Thus, we demonstrated that EI induced oxidative stress in endothelial cells leading to increased expression of oxidative stress response gene OKL38 and HO-1 via Nrf2 signaling pathway relevant to atherosclerosis.
authors.affiliation: Changzhou No. 2 People's Hospital, Diabetes Institute, 29 Xinglong Lane, Changzhou City, Jiangsu Prov. 213003, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Medicine, University of California, Los Angeles, 650 Charles Young Dr., Los Angeles, CA 90095, USA.
authors.forename: Sangderk
authors.initials: S
authors.lastname: Lee
authors.affiliation: Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: B Gabriel
authors.initials: BG
authors.lastname: Gugiu
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Ave, Los Angeles, CA 90095, USA.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Koroniak
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Ave, Los Angeles, CA 90095, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.affiliation: Department of Medicine, University of California, Los Angeles, 650 Charles Young Dr., Los Angeles, CA 90095, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Berliner
authors.affiliation: Changzhou No. 2 People's Hospital, Diabetes Institute, 29 Xinglong Lane, Changzhou City, Jiangsu Prov. 213003, China. Electronic address: chengjinluouu@sina.com.
authors.forename: Jinluo
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of California, Los Angeles, 650 Charles Young Dr., Los Angeles, CA 90095, USA; Department of Biomedical Engineering, University of Southern California Los Angeles, CA 90089, USA. Electronic address: rongsonl@usc.edu.
authors.forename: Rongsong
authors.initials: R
authors.lastname: Li
mesh_terms: D051017:Apoptosis Regulatory Proteins; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D028421:Isoprostanes / Q000378:metabolism / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010713:Phosphatidylcholines / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C500237:1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphocholine; D051017:Apoptosis Regulatory Proteins; D028421:Isoprostanes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C432368:OSGIN1 protein, human; D010713:Phosphatidylcholines; D011506:Proteins; D034741:RNA, Small Interfering; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Epoxyisoprostane E2 (EI); HO-1 oxidative stress; Nrf2; OKL38; OxPAPC; Oxidized phospholipids