title: Nrf2 antioxidant defense is involved in survival signaling elicited by 27-hydroxycholesterol in human promonocytic cells.
abstract: Cholesterol oxidation products such as oxysterols are considered critical factors in the atherosclerotic plaque formation since they induce oxidative stress, inflammation and apoptotic cell death. 27-hydroxycholesterol (27-OH) is one of the most represented oxysterols in atherosclerotic lesions. We recently showed that relatively low concentrations of 27-OH generated a strong survival signaling through an early and transient increase of cellular ROS level, that enhanced MEK-ERK/PI3K-Akt phosphorylation, in turn responsible of a sustained quenching of ROS production. It remains to identify the link between ERK/Akt up-regulation and the consequent quenching effect on ROS intracellular level that efficiently and markedly delay the pro-apoptotic effect of the oxysterol. Here we report on the potent activation of Nrf2 redox-sensitive transcription factor by low micromolar amount of 27-OH added to U937 promonocytic cells. The 27-OH-exerted induction of Nrf2 and subsequently of the target genes, HO-1 and NQO-1, was proved to be: (i) dependent upon the activation of ERK and Akt pathways, (ii) directly responsible for the quenching of intracellular oxidative stress and by this way (iii) ultimately responsible for the observed oxysterol-induced pro-survival response.
authors.affiliation: Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Orhanli-Tuzla, 34956 Istanbul, Turkey. Electronic address: beyzav@sabanciuniv.edu.
authors.forename: Beyza
authors.initials: B
authors.lastname: Vurusaner
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy. Electronic address: paola.gamba@unito.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Gamba
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy. Electronic address: simona.gargiulo@unito.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Gargiulo
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy. Electronic address: gabriella.testa@unito.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Testa
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Staurenghi
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy. Electronic address: gabriella.leonarduzzi@unito.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leonarduzzi
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy. Electronic address: giuseppe.poli@unito.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Poli
authors.affiliation: Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Orhanli-Tuzla, 34956 Istanbul, Turkey. Electronic address: huveyda@sabanciuniv.edu.
authors.forename: Huveyda
authors.initials: H
authors.lastname: Basaga
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D055017:Monocyte-Macrophage Precursor Cells / Q000187:drug effects / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species
chemical_list: D006888:Hydroxycholesterols; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C076996:27-hydroxycholesterol; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: 27-Hydroxycholesterol; Nrf2; Oxysterols; ROS; Survival signaling