Regulation of Antioxidants and Phase 2 Enzymes by Shear-Induced Reactive Oxygen Species in Endothelial Cells |
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Authors: | Charles I. Jones Suffix" >III,Hong Zhu,Sergio F. Martin,Zhaosheng Han,Yunbo Li,B. Rita Alevriadou |
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Affiliation: | (1) Department of Internal Medicine, Davis Heart and Lung Research Institute, Columbus, OH 43210, USA;(2) Department of Biomedical Engineering, The Ohio State University, 610 DHLRI, 473 West 12th Avenue, Columbus, OH 43210, USA;(3) Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA;(4) Present address: Centro de Investigación en Sanidad, Ctra. de Algete a El Casar, 28130 Valdeolmos, Madrid, Spain |
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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 (O2•−)/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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Keywords: | Steady laminar shear stress Oxidative stress Nitric oxide Reactive nitrogen species NF-E2-related factor 2 Antioxidant response element Glutathione-linked antioxidants |
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