title: Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling.
abstract: Secreted phospholipases A2 (sPLA2s) are present in atherosclerotic plaques and are now considered novel attractive therapeutic targets and potential biomarkers as they contribute to the development of atherosclerosis through lipoprotein-dependent and independent mechanisms. We have previously shown that hGX-sPLA2-phospholipolyzed LDL (LDL-X) induces proinflammatory responses in human umbilical endothelial cells (HUVECs); here we explore the molecular mechanisms involved. Global transcriptional gene expression profiling of the response of endothelial cells exposed to either LDL or LDL-X revealed that LDL-X activates multiple distinct cellular pathways including the unfolded protein response (UPR). Mechanistic insight showed that LDL-X activates UPR through calcium depletion of intracellular stores, which in turn disturbs cytoskeleton organization. Treatment of HUVECs and aortic endothelial cells (HAECs) with LDL-X led to activation of all 3 proximal initiators of UPR: eIF-2alpha, IRE1alpha, and ATF6. In parallel, we observed a sustained phosphorylation of the p38 pathway resulting in the phosphorylation of AP-1 downstream targets. This was accompanied by significant production of the proinflammatory cytokines IL-6 and IL-8. Our study demonstrates that phospholipolyzed LDL uses a range of molecular pathways including UPR to initiate endothelial cell perturbation and thus provides an LDL oxidation-independent mechanism for the initiation of vascular inflammation in atherosclerosis.
authors.affiliation: INSERM UMRS 937, Université Pierre et Marie Curie, UPMC-Paris 6, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gora
authors.forename: Seraya
authors.initials: S
authors.lastname: Maouche
authors.forename: Rajai
authors.initials: R
authors.lastname: Atout
authors.forename: Kristell
authors.initials: K
authors.lastname: Wanherdrick
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Ewa
authors.initials: E
authors.lastname: Ninio
authors.forename: Sonia-Athina
authors.initials: SA
authors.lastname: Karabina
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D054497:Phospholipases A2, Secretory; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology; D056811:Unfolded Protein Response
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D015852:Eukaryotic Initiation Factor-2; D015850:Interleukin-6; D016209:Interleukin-8; D008077:Lipoproteins, LDL; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D054497:Phospholipases A2, Secretory