title: Temporal Cross Talk Between Endoplasmic Reticulum and Mitochondria Regulates Oxidative Stress and Mediates Microparticle-Induced Endothelial Dysfunction.
abstract: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated.
  
  
  
  Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers, X-box binding protein 1, p-eukaryotic translation initiation factor 2 α, and CHOP, and nuclear translocation of activating transcription factor 6 on human aortic endothelial cells (HAoECs). MPs decreased in vitro nitric oxide release by HAoECs, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited, suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomyelinase (SMase) with siRNA abrogated all MP-mediated effects. Neutralization of Fas ligand carried by MPs abolished effects induced by both MP types, whereas neutralization of low-density lipoprotein receptor on endothelial cells prevented T-lymphocyte MP-mediated effects. Innovation and Conclusion: Collectively, endothelial dysfunction triggered by MPs involves temporal cross talk between ER and mitochondria with respect to spatial regulation of ROS via the neutral SMase and interaction of MPs with Fas and/or low-density lipoprotein receptor. These results provide a novel molecular insight into the manner MPs mediate vascular dysfunction and allow identification of potential therapeutic targets to treat vascular complications associated with metabolic syndrome. Antioxid. Redox Signal. 26, 15-27.
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .|2 ER045, Laboratory of Stem Cells, PRASE, DSST, Lebanese University , Beirut, Lebanon .
authors.forename: Zainab
authors.initials: Z
authors.lastname: Safiedeen
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez-Gómez
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .
authors.forename: Luisa
authors.initials: L
authors.lastname: Vergori
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soleti
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .
authors.forename: Dayannath
authors.initials: D
authors.lastname: Vaithilingam
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .
authors.forename: Imene
authors.initials: I
authors.lastname: Douma
authors.affiliation: 3 Faculty of Health and Medical Sciences, University of Surrey , Guildford, United Kingdom .
authors.forename: Abdelali
authors.initials: A
authors.lastname: Agouni
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .
authors.forename: Denis
authors.initials: D
authors.lastname: Leiber
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .|4 Centre Hospitalo-Universitaire d'Angers , Angers, France .
authors.forename: Séverine
authors.initials: S
authors.lastname: Dubois
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .|4 Centre Hospitalo-Universitaire d'Angers , Angers, France .
authors.forename: Gilles
authors.initials: G
authors.lastname: Simard
authors.affiliation: 2 ER045, Laboratory of Stem Cells, PRASE, DSST, Lebanese University , Beirut, Lebanon .|5 Faculty of Sciences-I, Biology Department, Lebanese University , Beirut, Lebanon .
authors.forename: Kazem
authors.initials: K
authors.lastname: Zibara
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .|4 Centre Hospitalo-Universitaire d'Angers , Angers, France .
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.affiliation: 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .|4 Centre Hospitalo-Universitaire d'Angers , Angers, France .
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Martínez
mesh_terms: D055252:Cell-Derived Microparticles / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D024821:Metabolic Syndrome / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D019014:fas Receptor; D013108:Sphingomyelin Phosphodiesterase
keywords: endoplasmic reticulum; endothelial dysfunction; extracellular vesicles; metabolic syndrome; mitochondria