title: Multi-targeted mechanisms underlying the endothelial protective effects of the diabetic-safe sweetener erythritol.
abstract: Diabetes is characterized by hyperglycemia and development of vascular pathology. Endothelial cell dysfunction is a starting point for pathogenesis of vascular complications in diabetes. We previously showed the polyol erythritol to be a hydroxyl radical scavenger preventing endothelial cell dysfunction onset in diabetic rats. To unravel mechanisms, other than scavenging of radicals, by which erythritol mediates this protective effect, we evaluated effects of erythritol in endothelial cells exposed to normal (7 mM) and high glucose (30 mM) or diabetic stressors (e.g. SIN-1) using targeted and transcriptomic approaches. This study demonstrates that erythritol (i.e. under non-diabetic conditions) has minimal effects on endothelial cells. However, under hyperglycemic conditions erythritol protected endothelial cells against cell death induced by diabetic stressors (i.e. high glucose and peroxynitrite). Also a number of harmful effects caused by high glucose, e.g. increased nitric oxide release, are reversed. Additionally, total transcriptome analysis indicated that biological processes which are differentially regulated due to high glucose are corrected by erythritol. We conclude that erythritol protects endothelial cells during high glucose conditions via effects on multiple targets. Overall, these data indicate a therapeutically important endothelial protective effect of erythritol under hyperglycemic conditions.
authors.affiliation: Department of Toxicology, Maastricht University, Maastricht, The Netherlands. danielle.boesten@maastrichtuniversity.nl
authors.forename: Daniëlle M P H J
authors.initials: DM
authors.lastname: Boesten
authors.forename: Alvin
authors.initials: A
authors.lastname: Berger
authors.forename: Peter
authors.initials: P
authors.lastname: de Cock
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Gertjan J M
authors.initials: GJ
authors.lastname: den Hartog
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000378:metabolism; D004896:Erythritol / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D018384:Oxidative Stress; D013549:Sweetening Agents / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D015777:Eicosanoids; D013549:Sweetening Agents; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D005947:Glucose; D004896:Erythritol