Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation

Peroxidation of plasma lipoproteins has been implicated in the endothelial cell activation and monocyte adhesion that initiate atherosclerosis, but the exact mechanisms underlying this activation remain unclear. Lipid peroxidation generates lipid aldehydes, including the gamma-ketoaldehydes (gamma KA), also termed isoketals or isolevuglandins, that readily modify the amine headgroup of phosphatidylethanolamine (PE). We hypothesized that aldehyde modification of PE could mediate some of the proinflammatory effects of lipid peroxidation. We found that PE modified by gamma KA (gamma KA-PE) induced THP-1 monocyte adhesion to human umbilical cord endothelial cells. gamma KA-PE also induced expression of adhesion molecules and increased MCP-1 and IL-8 mRNA in human umbilical cord endothelial cells. To determine the structural requirements for gamma KA-PE activity, we tested several related compounds. PE modified by 4-oxo-pentanal induced THP-1 adhesion, but N-glutaroyl-PE and C18:0N-acyl-PE did not, suggesting that an N-pyrrole moiety was essential for cellular activity. As the N-pyrrole headgroup might distort the membrane, we tested the effect of the pyrrole-PEs on membrane parameters. gamma KA-PE and 4-oxo-pentanal significantly reduced the temperature for the liquid crystalline to hexagonal phase transition in artificial bilayers, suggesting that these pyrrole-PE markedly altered membrane curvature. Additionally, fluorescently labeled gamma KA-PE rapidly internalized to the endoplasmic reticulum (ER); gamma KA-PE induced C/EBP homologous protein CHOP and BiP expression and p38 MAPK activity, and inhibitors of ER stress reduced gamma KA-PE-induced C/EBP homologous protein CHOP and BiP expression as well as EC activation, consistent with gamma KA-PE inducing ER stress responses that have been previously linked to inflammatory chemokine expression. Thus, gamma KA-PE is a potential mediator of the inflammation induced by lipid peroxidation.