title: Endoplasmic reticulum stress mediates the anti-inflammatory effect of ethyl pyruvate in endothelial cells.
abstract: Ethyl pyruvate (EP) is a simple aliphatic ester of the metabolic intermediate pyruvate that has been demonstrated to be a potent anti-inflammatory agent in a variety of in vivo and in vitro model systems. However, the protective effects and mechanisms underlying the actions of EP against endothelial cell (EC) inflammatory injury are not fully understood. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of EC inflammation. In this study, our aim was to explore the effects of EP on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human umbilical vein endothelial cells (HUVECs) and to explore the role of ERS in this process. TNF-α treatment not only significantly increased the adhesion of monocytes to HUVECs and inflammatory cytokine (sICAM1, sE-selectin, MCP-1 and IL-8) production in cell culture supernatants but it also increased ICAM and MMP9 protein expression in HUVECs. TNF-α also effectively increased the ERS-related molecules in HUVECs (GRP78, ATF4, caspase12 and p-PERK). EP treatment effectively reversed the effects of the TNF-α-induced adhesion of monocytes on HUVECs, inflammatory cytokines and ERS-related molecules. Furthermore, thapsigargin (THA, an ERS inducer) attenuated the protective effects of EP against TNF-α-induced inflammatory injury and ERS. The PERK siRNA treatment not only inhibited ERS-related molecules but also mimicked the protective effects of EP to decrease TNF-α-induced inflammatory injury. In summary, we have demonstrated for the first time that EP can effectively reduce vascular endothelial inflammation and that this effect at least in part depends on the attenuation of ERS.
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China; Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Basic Medical Sciences, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Air Logistics, The 463rd Hospital of PLA, 46 Xiaoheyan Road, Shenyang 110042, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Dajun
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.
authors.forename: Chongxi
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China.
authors.forename: Honggang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Geng
authors.affiliation: Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China.
authors.forename: Jianzhou
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China.
authors.forename: Songtao
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Dinghua
authors.initials: D
authors.lastname: Yi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D053454:Caspase 12 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011773:Pyruvates / Q000494:pharmacology*; D034622:RNA Interference; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D000893:Anti-Inflammatory Agents; D053454:Caspase 12; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C000717247:HSPA5 protein, human; C046522:ethyl pyruvate