Endoplasmic reticulum stress mediates the anti-inflammatory effect of ethyl pyruvate in endothelial cells

PLoS One. 2014 Dec 3;9(12):e113983. doi: 10.1371/journal.pone.0113983. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Anti-Inflammatory Agents / pharmacology*
  • Blotting, Western
  • Caspase 12 / metabolism
  • Cell Adhesion / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytokines / metabolism
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects*
  • Heat-Shock Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Monocytes / pathology
  • Pyruvates / pharmacology*
  • RNA Interference
  • Tumor Necrosis Factor-alpha / pharmacology
  • U937 Cells
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism


  • ATF4 protein, human
  • Anti-Inflammatory Agents
  • Cytokines
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Inflammation Mediators
  • Pyruvates
  • Tumor Necrosis Factor-alpha
  • ethyl pyruvate
  • Intercellular Adhesion Molecule-1
  • Activating Transcription Factor 4
  • PERK kinase
  • eIF-2 Kinase
  • Caspase 12
  • Matrix Metalloproteinase 9

Grant support

This study was supported by grants from the 12th National Five Years Supporting Project of China (2011BAI11B20), the National Natural Science Foundation of China (81100137 and 81000938). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.