Alkyl-glycerophosphate-mediated C-C motif chemokine 2 secretion induces oxidative stress via increased PPARγ activation in human umbilical vein endothelial cells

Biomed Pharmacother. 2018 Oct;106:686-691. doi: 10.1016/j.biopha.2018.07.012. Epub 2018 Jul 11.

Abstract

We previously showed that an alkyl-ether analog of lysophosphatidic acid, AGP (alkyl-glycerophosphate), accumulates in human atherosclerotic plaques and is a potent agonist of peroxisome proliferator-activated receptor-gamma (PPARγ). On the other hand, cyclic phosphatidic acid (cPA), similar in structure to AGP, can negatively regulate PPARγ. However, in this study, cPA had no effect on the expression and secretion of C-C motif chemokine 2 (CCL-2), a chemokine that is also linked to inflammatory responses and atherosclerosis. We showed that AGP enhances CCL-2 mRNA expression and secretion in a dose-dependent manner. Furthermore, oxidative stress plays a major role in the pathology of cardiovascular diseases; we showed that AGP triggers ROS generation and lipid peroxidation and that ROS and 8-isoprostane generation can be suppressed by a PPARγ antagonist. These results suggest that an imbalance of the PPARγ agonist-antagonist equilibrium is involved in changes in cellular functions, including ROS generation and lipid peroxidation.

Keywords: AGP; CCL-2; PPARγ; Peroxidation; ROS.

MeSH terms

  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Dinoprost / analogs & derivatives
  • Dinoprost / metabolism
  • Dose-Response Relationship, Drug
  • Glycerophosphates / pharmacology*
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Lipid Peroxidation / drug effects
  • Lysophospholipids / pharmacology*
  • Oxidative Stress / drug effects*
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Phosphatidic Acids / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Up-Regulation

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • Glycerophosphates
  • Lysophospholipids
  • PPAR gamma
  • Phosphatidic Acids
  • Reactive Oxygen Species
  • 8-epi-prostaglandin F2alpha
  • Dinoprost