title: Oxidized LDL attenuates protective autophagy and induces apoptotic cell death of endothelial cells: Role of oxidative stress and LOX-1 receptor expression.
abstract: BACKGROUND
  Overproduction of oxidized-low density lipoproteins (oxyLDLs) has been found to contribute in endothelial cell (EC) dysfunction thereby leading to atherosclerosis development and progression. In particular, oxyLDLs lead to apoptotic cell death of EC via oxidative stress production, mostly subsequent to the overexpression of the scavenger receptor LOX-1. Here, we hypothesize that LOX-1 expression in EC represents a crucial event which attenuates protective autophagic response, thereby enhancing programmed endothelial cell death.
  
  
  RESULTS
  Bovine aortic endothelial cells (BAECs) in culture were exposed to oxyLDL (1-100 μM). After 48 h incubation, oxyLDL produced pronounced malondialdehyde (MDA) elevation and apoptotic cell death of BAEC as detected by FACS analysis, an effect counteracted by antioxidant N-acetyl-cysteine (NAC) as well as by the NO-donor SNAP. OxyLDL-induced apoptotic cell death was also accompanied by reduced VEGF-dependent phosphorylation of constitutive NO synthase (cNOS) in BAEC and consistent attenuation of autophagic response as detected by the expression of Beclin-1 and LC3, two reliable biomarkers of autophagy. Moreover, silencing LOX-1 receptor significantly restored LC3 expression in oxyLDL-treated BAEC, thus suggesting a key role of LOX-1 overproduction in oxyLDL-induced endothelial dysfunction.
  
  
  CONCLUSIONS
  OxyLDL leads to impaired NO generation and apoptotic cell death in BAECs. This effect occurs via the overexpression of LOX-1 and subsequent attenuation of protective autophagic response thereby contributing to the pathophysiology of oxyLDL-induced endothelial dysfunction which characterizes early stages of atherosclerotic process.
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy; IRCCS San Raffaele, Rome, Italy. Electronic address: mollace@libero.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mollace
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Micaela
authors.initials: M
authors.lastname: Gliozzi
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Musolino
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Carresi
authors.affiliation: Department of Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Muscoli
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Mollace
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Tavernese
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Santo
authors.initials: S
authors.lastname: Gratteri
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Palma
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Morabito
authors.affiliation: IRCCS San Raffaele, Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Vitale
authors.affiliation: IRC-FSH Department of Health Sciences, University "Magna Græcia" of Catanzaro, Italy; IRCCS San Raffaele, Rome, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.affiliation: IRCCS San Raffaele, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Fini
authors.affiliation: Department of Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Romeo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D008077:Lipoproteins, LDL / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis*
chemical_list: D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein
keywords: LOX-1; Oxidative stress; Oxidized-LDL; Protective autophagy