title: Rutin protects against H2O2-triggered impaired relaxation of placental arterioles and induces Nrf2-mediated adaptation in Human Umbilical Vein Endothelial Cells exposed to oxidative stress.
abstract: Rutin intake is associated with a reduced risk of cardiovascular disease (CVD). The exact mechanism by which rutin can protect against CVD development is still enigmatic. Since, rutin is a compound with a relatively short half-life, the direct antioxidant effect of rutin cannot explain the long-lasting effect on human health. We hypothesized that rutin next to its direct antioxidant effect that improves endothelial function, may also induce an adaptive response in endogenous antioxidant systems.
  
  
  
  In Human Umbilical Vein Endothelial Cells (HUVECs), the direct antioxidant effect was confirmed. During scavenging of Reactive Oxygen Species (ROS), rutin is oxidized into a quinone derivative. HUVECs pretreated with rutin quinone became better protected against a second challenge with oxidative stress 3h later. LC-MS/MS analysis indicated that rutin quinone targets cysteine 151 of Keap1. Moreover, we found that the quinone is an inhibitor of the selenoprotein thioredoxin reductase 1. These properties correlated with an activation of Nrf2 and upregulation of Glutamate Cysteine Ligase, the rate-limiting enzyme of glutathione synthesis, while NF-κB and HIF activation became blunted by rutin treatment. Furthermore, rutin was found to prevent hydrogen peroxide from impairing relaxation of human chorionic plate placental vessels, which may help to protect endothelial function.
  
  
  
  Rutin functions as an antioxidant and is oxidized into a quinone that upregulates the Nrf2-mediated endogenous antioxidant response. This mechanism suggests that rutin selectively exerts its protective effects in regions with increased oxidative stress, and explains how rutin reduces the risk of developing CVD.
  
  
  
  The newly found mechanism behind the long-term protection of rutin against cardiovascular disease, the selective upregulation of endogenous antioxidant systems, contributes to the further understanding why rutin can reduce the risk on developing cardiovascular disease.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: mireille.sthijns@maastrichtuniversity.nl.
authors.forename: Mireille M J P E
authors.initials: MMJPE
authors.lastname: Sthijns
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: p.schiffers@maastrichtuniversity.nl.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Schiffers
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: g.janssen@maastrichtuniversity.nl.
authors.forename: Ger M
authors.initials: GM
authors.lastname: Janssen
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: kristien.lemmens@mumc.nl.
authors.forename: Kristien J A
authors.initials: KJA
authors.lastname: Lemmens
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: bart_ides@hotmail.com.
authors.forename: Bart
authors.initials: B
authors.lastname: Ides
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: p.vangrieken@maastrichtuniversity.nl.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vangrieken
authors.affiliation: Department of Human Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: freek.bouwman@maastrichtuniversity.nl.
authors.forename: Freek G
authors.initials: FG
authors.lastname: Bouwman
authors.affiliation: Department of Human Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: e.mariman@maastrichtuniversity.nl.
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Mariman
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: irina.pader@gmail.com.
authors.forename: Irina
authors.initials: I
authors.lastname: Pader
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Elias.Arner@ki.se.
authors.forename: Elias S J
authors.initials: ESJ
authors.lastname: Arnér
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Katarina.Johansson@ki.se.
authors.forename: Katarina
authors.initials: K
authors.lastname: Johansson
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: a.bast@maastrichtuniversity.nl.
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: g.haenen@maastrichtuniversity.nl.
authors.forename: Guido R M M
authors.initials: GRMM
authors.lastname: Haenen
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000975:Antioxidants / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D057809:HEK293 Cells; D006207:Half-Life; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D020011:Protective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012431:Rutin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D020011:Protective Agents; D017382:Reactive Oxygen Species; D012431:Rutin; D006861:Hydrogen Peroxide; D005721:Glutamate-Cysteine Ligase
keywords: Adaptation; Endothelial function; Flavonoids; Nrf2; Rutin