title: Statins Prevent Dextrose-Induced Endoplasmic Reticulum Stress and Oxidative Stress in Endothelial and HepG2 Cells.
abstract: Statins have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. However, antioxidant vitamins, unlike statins, are not as cardioprotective, and this paradox has been explained by failure of vitamin antioxidants to ameliorate endoplasmic reticulum (ER) stress. To determine whether statins prevent dextrose-induced ER stress in addition to their antioxidative effects, human umbilical vein endothelial cells and HepG2 hepatocytes were treated with 27.5 mM dextrose in the presence of simvastatin (lipophilic statin that is a prodrug) and pravastatin (water-soluble active drug), and oxidative stress, ER stress, and cell death were measured. Superoxide generation was measured using 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride. ER stress was measured using the placental alkaline phosphatase assay and Western blot of glucose-regulated protein 75, c-jun-N-terminal kinase, phospho-JNK, eukaryotic initiating factor 2α and phospho-eIF2α, and X-box binding protein 1 mRNA splicing. Cell viability was measured by propidium iodide staining. Superoxide anion production, ER stress, and cell death induced by 27.5 mM dextrose were inhibited by therapeutic concentrations of simvastatin and pravastatin. The salutary effects of statins on endothelial cells in reducing both ER stress and oxidative stress observed with pravastatin and the prodrug simvastatin suggest that the effects may be independent of cholesterol-lowering activity.
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Jacksonville, FL.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kojanian
authors.forename: Anna
authors.initials: A
authors.lastname: Szafran-Swietlik
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Onstead-Haas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005947:Glucose / Q000633:toxicity; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017035:Pravastatin / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013481:Superoxides; D019821:Simvastatin; D005947:Glucose; D017035:Pravastatin