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Biochim Biophys Acta Gen Subj. 2017 May;1861(5 Pt A):1177-1189. doi: 10.1016/j.bbagen.2017.03.004. Epub 2017 Mar 7.

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.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
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.
7
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.
8
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.
9
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: irina.pader@gmail.com.
10
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Elias.Arner@ki.se.
11
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Katarina.Johansson@ki.se.
12
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.
13
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.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSION AND SIGNIFICANCE:

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.

GENERAL SIGNIFICANCE:

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.

KEYWORDS:

Adaptation; Endothelial function; Flavonoids; Nrf2; Rutin

PMID:
28286015
DOI:
10.1016/j.bbagen.2017.03.004
[Indexed for MEDLINE]

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