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Regulation of Antioxidants and Phase 2 Enzymes by Shear-Induced Reactive Oxygen Species in Endothelial Cells

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Abstract

Exposure of vascular endothelial cells (ECs) to steady laminar shear stress activates the NF-E2-related factor 2 (Nrf2) which binds to the antioxidant response element (ARE) and upregulates the expression of several genes. The onset of shear is known to increase the EC reactive oxygen species (ROS) production, and oxidative stress can activate the ARE. ARE-regulated genes include phase 2 enzymes, such as glutathione-S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and antioxidants, such as glutathione reductase (GR), glutathione peroxidase (GPx) and catalase. We examined how shear stress affects the antioxidant/phase 2 enzyme activities and whether ROS mediate these effects. ROS production, measured by dichlorofluorescin fluorescence, depended on level and time of shear exposure and EC origin, and was inhibited by either an endothelial nitric oxide synthase (eNOS) inhibitor or a superoxide dismutase (SOD) mimetic and peroxynitrite (ONOO−) scavenger. Shear stress (10 dynes/cm2, 16 h) significantly increased the NQO1 activity, did not change significantly the glutathione (GSH) content, and significantly decreased the GR, GPx, GST and catalase activities in human umbilical vein ECs. Either eNOS inhibition or superoxide radical (O •−2 )/ONOO− scavenging differentially modulated the shear effects on enzyme activities suggesting that the intracellular redox status coordinates the shear-induced expression of cytoprotective genes.

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Abbreviations

EC:

endothelial cell

Nrf2:

NF-E2-related factor 2

ARE:

antioxidant response element

ROS:

reactive oxygen species

GSH:

glutathione

GST:

glutathione-S-transferase

NQO1:

NAD(P)H:quinone oxidoreductase 1

GR:

glutathione reductase

GPx:

glutathione peroxidase

eNOS:

endothelial nitric oxide synthase

SOD:

superoxide dismutase

ONOO− :

peroxynitrite

O •−2 :

superoxide radical

VCAM-1:

vascular cell adhesion molecule-1

HO-1:

heme oxygenase-1

γ-GCS:

γ-glutamylcysteine synthetase

NO:

nitric oxide

HUVECs:

human umbilical vein ECs

H2O2 :

hydrogen peroxide

GSSG:

glutathione disulfide

O2 :

molecular oxygen

RNS:

reactive nitrogen species

l-NAME:

N G-nitro-l-arginine methyl ester

MnTBAP:

Mn(III) tetrakis(4-benzoic acid) porphyrin

HMVECs:

human microvascular ECs

DCFH-DA:

2′,7′-dichlorodihydrofluorescein diacetate

DCF:

dichlorofluorescin

NO •2 :

nitrogen dioxide radical

NAC:

N-acetylcysteine

PDTC:

pyrrolidine dithiocarbamate

FBS:

fetal bovine serum

CDNB:

1-chloro-2,3-dinitrobenzene

DCIP:

dichloroindophenol

HAECs:

human aortic ECs

Keap1:

Kelch-like ECH-associated protein 1

GS:

glutamyl synthase

LOOH:

lipid hydroperoxide

ONOOH:

peroxynitrous acid

OH• :

hydroxyl radical

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Acknowledgments

This study was supported by National Institutes of Health Grants HL67027 (B. R. Alevriadou) and HL71190 (Y. Li). We thank Mr. Guruguhan Meenakshisundaram for statistical analysis.

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  1. Sergio F. Martin

    Present address: Centro de Investigación en Sanidad, Ctra. de Algete a El Casar, 28130, Valdeolmos, Madrid, Spain

Authors and Affiliations

  1. Department of Internal Medicine, Davis Heart and Lung Research Institute, Columbus, OH, 43210, USA

    Charles I. Jones III, Hong Zhu, Zhaosheng Han, Yunbo Li & B. Rita Alevriadou

  2. Department of Biomedical Engineering, The Ohio State University, 610 DHLRI, 473 West 12th Avenue, Columbus, OH, 43210, USA

    Charles I. Jones III, Zhaosheng Han & B. Rita Alevriadou

  3. Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, 21205, USA

    Sergio F. Martin

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Jones, C.I., Zhu, H., Martin, S.F. et al. Regulation of Antioxidants and Phase 2 Enzymes by Shear-Induced Reactive Oxygen Species in Endothelial Cells. Ann Biomed Eng 35, 683–693 (2007). https://doi.org/10.1007/s10439-007-9279-9

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