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

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.