title: Vitamin D protects human endothelial cells from oxidative stress through the autophagic and survival pathways.
abstract: BACKGROUND
  Recently, vitamin D (VitD) has been recognized as increasingly importance in many cellular functions of several tissues and organs other than bone. In particular, VitD showed important beneficial effects in the cardiovascular system. Although the relationship among VitD, endothelium, and cardiovascular disease is well established, little is known about the antioxidant effect of VitD.
  
  
  OBJECTIVE
  Our objective was to study the intracellular pathways activated by VitD in cultured human umbilical vein endothelial cells undergoing oxidative stress.
  
  
  METHODS
  Nitric oxide production, cell viability, reactive oxygen species, the mitochondrial permeability transition pore, membrane potential, and caspase-3 activity were measured during oxidative stress induced by administration of 200 μM hydrogen peroxide for 20 minutes. Experiments were repeated in the presence of specific vitamin D receptor ligand ZK191784.
  
  
  RESULTS
  Pretreatment with VitD alone or in combination with ZK191784 is able to reduce the apoptosis-related gene expression, involving both intrinsic and extrinsic pathways. At the same time, it has been shown the activation of pro-autophagic beclin 1 and the phosphorylation of ERK1/2 and Akt, indicating a modulation between apoptosis and autophagy. Moreover, VitD alone or in combination with ZK191784 is able to prevent the loss of mitochondrial potential and the consequent cytochrome C release and caspase activation.
  
  
  CONCLUSIONS
  The present study shows that VitD may prevent endothelial cell death through modulation of the interplay between apoptosis and autophagy. This effect is obtained by inhibiting superoxide anion generation, maintaining mitochondria function and cell viability, activating survival kinases, and inducing NO production.
authors.affiliation: Department of Obstetrics and Gynecology (F.U., D.L., V.M., U.N.), Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; Dipartimento di Scienze Cliniche e di Comunità (G.B.), Università degli Studi di Milano, 20122, Milan, Italy Dipartimento di Medicina Traslazionale (V.M., G.V., D.F.S., C.M.), Università degli Studi del Piemonte Orientale A. Avogadro, 28100 Novara, Italy; and Dipartimento di Scienze della Salute (C.C.), Università degli Studi del Piemonte Orientale A. Avogadro, 28100 Novara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Uberti
authors.forename: D
authors.initials: D
authors.lastname: Lattuada
authors.forename: V
authors.initials: V
authors.lastname: Morsanuto
authors.forename: U
authors.initials: U
authors.lastname: Nava
authors.forename: G
authors.initials: G
authors.lastname: Bolis
authors.forename: G
authors.initials: G
authors.lastname: Vacca
authors.forename: D F
authors.initials: DF
authors.lastname: Squarzanti
authors.forename: C
authors.initials: C
authors.lastname: Cisari
authors.forename: C
authors.initials: C
authors.lastname: Molinari
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D014807:Vitamin D; D009569:Nitric Oxide; D006861:Hydrogen Peroxide