title: Phosphatidylethanolamines modified by γ-ketoaldehyde (γKA) induce endoplasmic reticulum stress and endothelial activation.
abstract: 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 γ-ketoaldehydes (γKA), 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 γKA (γKA-PE) induced THP-1 monocyte adhesion to human umbilical cord endothelial cells. γKA-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 γKA-PE activity, we tested several related compounds. PE modified by 4-oxo-pentanal induced THP-1 adhesion, but N-glutaroyl-PE and C(18:0)N-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. γKA-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 γKA-PE rapidly internalized to the endoplasmic reticulum (ER); γKA-PE induced C/EBP homologous protein CHOP and BiP expression and p38 MAPK activity, and inhibitors of ER stress reduced γKA-PE-induced C/EBP homologous protein CHOP and BiP expression as well as EC activation, consistent with γKA-PE inducing ER stress responses that have been previously linked to inflammatory chemokine expression. Thus, γKA-PE is a potential mediator of the inflammation induced by lipid peroxidation.
authors: Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-6602, USA.
authors: Lilu
authors: L
authors: Guo
authors: Zhongyi
authors: Z
authors: Chen
authors: Brian E
authors: BE
authors: Cox
authors: Venkataraman
authors: V
authors: Amarnath
authors: Raquel F
authors: RF
authors: Epand
authors: Richard M
authors: RM
authors: Epand
authors: Sean S
authors: SS
authors: Davies
mesh_terms: D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004721:Endoplasmic Reticulum; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008051:Lipid Bilayers; D015227:Lipid Peroxidation; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D016209:Interleukin-8; D008051:Lipid Bilayers; D010714:Phosphatidylethanolamines; D051742:Transcription Factor CHOP; C483858:phosphatidylethanolamine