title: Vitamin D protects human endothelial cells from H₂O₂ oxidant injury through the Mek/Erk-Sirt1 axis activation.
abstract: Endothelium homeostasis alterations govern the pathogenesis of cardiovascular diseases. Several studies show that vitamins anti-oxidant proprieties rescue the endothelial functions adversely affected by oxidative stress in several diseases. We investigated the vitamin D anti-oxidant potential in human endothelial cells exposed to H2O2 oxidative stress. Vitamin D protected endothelial cells against H2O2 oxidative stress counteracting the superoxide anion generation, the apoptosis and blocking the extrinsic caspase cascade by positively controlling phospho-active ERKs level. MEKs/ERKs inhibitor U0126 reverted the vitamin D anti-oxidant effects. Characterizing the vitamin D downstream effector, we found that vitamin D up-regulated SirT-1 and reverted the SirT-1 down-regulation induced by H2O2. ERKs activation by vitamin D strictly correlated with SirT-1 protein accumulation since both MEKs/ERKs inhibition and ERK1/2 silencing decreased SIRT-1. SirT-1 inhibition by Sirtinol reverted the vitamin D anti-oxidant effects. Thus, vitamin D significantly reduced the endothelial malfunction and damage caused by oxidative stress, through the activation of MEKs/ERKs/SirT-1 axis.
authors.affiliation: Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy. lorellapolidoro@gmail.com
authors.forename: Lorella
authors.initials: L
authors.lastname: Polidoro
authors.forename: G
authors.initials: G
authors.lastname: Properzi
authors.forename: F
authors.initials: F
authors.lastname: Marampon
authors.forename: G L
authors.initials: GL
authors.lastname: Gravina
authors.forename: C
authors.initials: C
authors.lastname: Festuccia
authors.forename: E
authors.initials: E
authors.lastname: Di Cesare
authors.forename: L
authors.initials: L
authors.lastname: Scarsella
authors.forename: C
authors.initials: C
authors.lastname: Ciccarelli
authors.forename: B M
authors.initials: BM
authors.lastname: Zani
authors.forename: C
authors.initials: C
authors.lastname: Ferri
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014807:Vitamin D / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D013481:Superoxides; D014807:Vitamin D; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D020169:Caspases; C447939:SIRT1 protein, human; D056564:Sirtuin 1