title: Inhibition of endoplasmic reticulum stress and oxidative stress by vitamin D in endothelial cells.
abstract: Endoplasmic reticulum (ER) stress and oxidative stress promote endothelial dysfunction and atherosclerosis. Since vitamin D has been shown in several studies to lower the risk of cardiovascular disease, we examined the effects of vitamin D on ER stress and oxidative stress in endothelial cells. ER stress was measured using the placental secreted alkaline phosphatase assay and oxidative stress was measured by hydroethidine fluorescence. Expression of ER stress markers, including glucose-regulated protein 78, c-jun N-terminal kinase 1 phosphorylation, and eukaryotic initiation factor 2α phosphorylation, as well as X-box binding protein-1 splicing were measured in tunicamycin (TM)-treated human umbilical endothelial cells (HUVEC) treated with 1,25-dihydroxyvitamin D3(1,25-(OH)2D3) and other vitamin D analogs. When TM and 1,25-(OH)2D3were added simultaneously, 1,25-(OH)2D3prevented ER stress. However, the effect was much stronger when cells were pre-treated with 1,25-(OH)2D3for 24-h. However, ER stress was not inhibited by 25-OH vitamin D3(25-OHD3) or the vitamin D analog EB1089. Both ZK191784 and the vitamin D metabolite 24,25-dihydroxyvitamin D3were as effective as 1,25-(OH)2D3in preventing ER stress. Similar effects were observed dextrose-induced stress. All of the compounds tested, except for 25-OHD3, inhibited dextrose-induced (27.5mM) oxidative stress and ER stress. Although TM with and without 1,25-(OH)2D3had no effect on VDR expression, inhibition of VDR expression via siRNA prevented 1,25-(OH)2D3, ZK191784, EB1089, and 24,25-dihydroxyvitamin D3from inhibiting dextrose-mediated SO generation. Furthermore, each vitamin D analog, with the exception of 25-OHD3, prevented dextrose-induced toxicity. These results suggest that vitamin D has a protective effect on vascular endothelial cells.
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States. Electronic address: michael.haas@jax.ufl.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jafri
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.
authors.forename: Kent R
authors.initials: KR
authors.lastname: Wehmeier
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Onstead-Haas
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D000071717:X-Box Binding Protein 1; C470666:ZK 191784; D014415:Tunicamycin; D014807:Vitamin D; D015650:24,25-Dihydroxyvitamin D 3; C104450:25-hydroxyvitamin D; D048031:JNK Mitogen-Activated Protein Kinases; D002117:Calcitriol; D005947:Glucose; C078903:seocalcitol
keywords: 1,25-dihydroxyvitamin D(3); Cardiovascular disease; Endoplasmic reticulum stress; Endothelial cells